Dysregulated stress responsivity has been linked with weight gain in healthy samples. However, the relationship between disturbances in stress-related biology and changes in weight in people with type 2 diabetes (T2D) is unclear. A total of 66 participants with T2D underwent laboratory stress-testing in 2011–2012. Cardiovascular, neuroendocrine and inflammatory responses to standardised mental stress were assessed, and Body Mass Index (BMI) was measured. Participants self-reported information on BMI in 2019. Associations between stress-related biological responses and BMI at follow-up were modelled using linear regression adjusting for age, sex, resting biological levels and baseline BMI. Blunted diastolic blood pressure reactivity (B = −0.092, 95% CI -0.177; −0.007, p = 0.034) as well as poorer systolic blood pressure (B = −0.050, 95% CI -0.084; − 0.017, p = 0.004), diastolic blood pressure (B = −0.068, 95% CI -0.132; −0.004, p = 0.034) and heart rate (B = -0.122, 95% CI -0.015;-0.230, p = 0.027) recovery post-stress were associated with higher BMI 7.5 years later. Greater interleukin-1 receptor antagonist (B = 16.93, 95% CI 6.20; 27.67, p = 0.003) and monocyte chemoattractant protein-1 reactivity (B = 0.04, 95% CI 0.002; 0.084, p = 0.041) were associated with weight gain. No significant associations were detected for interleukin-6 or laboratory cortisol measures. Disturbances in stress-related biology may promote weight gain in people with T2D. Research with a larger sample size is required to explore associations between stress responsivity and BMI in people with T2D. • Obesity is common in diabetes and increases the risk of diabetes-complications. • We assessed stress responses and later body mass index (BMI) in diabetes. • Blunted cardiovascular reactivity and poor heart rate recovery are linked with weight gain. • Greater inflammatory responses are linked with higher BMI 7.5 years later. • Disturbed stress-related biology may promote weight gain in diabetes. [ABSTRACT FROM AUTHOR]