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Patients with colorectal cancer (CRC) are at high risk of frailty, leading to reduced quality of life and survival. Diet is associated with frailty in the elderly through regulating inflammation. Thus, we hypothesized that dietary inflammatory potential (as assessed by dietary inflammatory index [DII]) might be associated with frailty in patients with CRC through regulating inflammatory biomarkers. A total of 231 patients with CRC were included in this cross-sectional study. Dietary intake was evaluated by 3-day, 24-hour dietary recalls, and frailty status was assessed in accordance with the Fried frailty criteria. Plasma inflammatory cytokines were determined in 126 blood samples. A total of 67 patients (29.0%) were frail, with significantly higher DII scores than nonfrail patients, accompanied with significantly increased interleukin-6 (IL-6) and decreased interleukin-10 (IL-10) concentrations. Each 1-point increase of DII was related to a 25.0% increased risk of frailty. IL-6 was positively correlated with frailty and DII, whereas IL-10 was negatively correlated. After adjusting for age, sex, body mass index, education level, smoking status, and energy, mediation analysis revealed that the association between DII and frailty was significantly mediated by IL-6 (average causal mediation effect [ACME], 0.052; 95% confidence interval, 0.020–0.087; P =.002) and IL-10 (ACME, 0.025; 95% confidence interval, 0.004–0.063; P =.016). The ρ values for the sensitivity measure at which estimated ACMEs were zero were 0.3 and –0.2 for IL-6 and IL-10, respectively. Therefore, a pro-inflammatory diet was associated with frailty in patients with CRC possibly in part by affecting circulating IL-6 and IL-10 concentrations. In a sample of 231 patients with colorectal cancer, compared with nonfrail patients, frail patients consumed more pro-inflammatory diets indicated by higher DII scores and had higher plasma IL-6 and lower IL-10 concentrations. Higher DII was associated with increased risk of frailty. IL-6 was positively correlated with frailty and DII, whereas IL-10 was negatively correlated. Mediation analysis showed that the association between DII and frailty might be mediated in part by IL-6 and IL-10. Abbreviations : DII, dietary inflammatory index; IL-6, interleukin 6; IL-10, interleukin 10. [Display omitted] • 29.0% (67/231) patients with colorectal cancer were frail and 71.0% were non-frail. • Frail colorectal cancer patients consumed lower macronutrients and micronutrients. • Frail colorectal cancer patients had a higher dietary inflammatory index score. • A higher dietary inflammatory index was associated with a higher risk of frailty. • IL-6 and IL-10 were mediators in the association between diet and frailty. [ABSTRACT FROM AUTHOR]