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Background Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. Methods and findings We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. Conclusions These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860. Jakub G Sobiecki and team aim to develop a biomarker score able to discriminate between Mediterranean diet and habitual diet, and test its association with incident type 2 diabetes in a European cohort. Author summary Why was this study done? Epidemiological evidence has indicated that greater self-reported adherence to the Mediterranean diet may be associated with lower risk of new onset type 2 diabetes (T2D), but there has been uncertainty about the magnitude of association due to subjective reporting of diet. A combination of nutritional biomarkers could better assess diet–disease associations, but this approach has rarely been considered for overall diet quality, particularly for the association between the Mediterranean diet and T2D. What did the researchers do and find? Blood carotenoids and fatty acids can be used as an objective measure of adherence to the Mediterranean diet, as indicated by results from a trial (n = 128) of adopting Mediterranean diet with provision of its key foods to study participants. These biomarkers discriminated well between the trial participants under the Mediterranean diet intervention and those randomised to continuation of habitual diet (C-statistic = 0.88). In a study across 8 European countries (n = 22,202), adherence to the Mediterranean diet, estimated using a combination of nutritional biomarkers, was associated with lower risk of new onset T2D, with a stronger relationship compared to that with self-reported Mediterranean diet. The hazard ratios (HRs) (95% confidence interval (CI)) per standard deviation of adherence were 0.71 (0.65 to 0.77) and 0.90 (0.86 to 0.95), respectively. What do these findings mean? Adherence to the Mediterranean diet may be more beneficial for the primary prevention of T2D than previously estimated from observational dietary studies. Even small upward differences in objectively measured Mediterranean diet may be associated with a sizeable reduction of the risk of T2D at the population level. Causal interpretation of these findings is limited by potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding.