Abstract Background Major depressive disorder (MDD) is a severe, heritable psychiatric disorder associated with shortened lifespan and comorbidities of advancing age. It is unknown however whether MDD is associated with accelerated biological ageing relative to chronological age. This hypothesis was tested using the epigenetic clock as a measure of biological age. Methods To address the main hypothesis, using peripheral blood, we derived measures of Epigenetic Age Acceleration (EAA) in 3,833 controls and 1,219 MDD cases based on Hannum and Horvath epigenetic clocks in Generation Scotland (GS:SFHS, mean age 48 years, std dev 14.5). Models controlled for relatedness, sex, cell counts, and processing batch (basic model), as well as additional covariates of smoking and drinking status, and body mass index (BMI) (full models). Results Accelerated epigenetic ageing was found in MDD cases versus controls using the Horvath clock (β=0.0804, p=0.012 equivalent to 0.20 years) in both the basic and full models. Significant MDD*age interactions indicated greatest effects at younger age ranges. No significant differences were observed for the Hannum clock. BMI was the only additional covariate found to attenuate the relationship between EAA Horvath and MDD. Further, genetic correlation analysis indicated significant overlap in the genetic aetiology of EAA Horvath with BMI (r G =0.20, p=0.03), between MDD with BMI (r G =0.10, p=9.86×10 −6 ), but not between EAA Horvath and MDD (r G =0.14, p=0.125). Mediation analysis indicated partial mediation of the relationship between EAA Horvath and depression status through BMI (β =0.0028; p=0.0248, ~13%). Conclusion These data imply that accelerated biological ageing is associated with MDD and partially mediated through BMI.