Background: Modifiable cardiovascular risk factors elevate risk of subsequent depression in older adults, but the effect of their onset before or after age 65 on incident depression is unclear. Methods: Participants were 1190 male medical students without a diagnosis of depression, who matriculated in 1948-1964 and followed through 2011. Cox proportional hazards models were used to assess associations of vascular risk-factor burden, diabetes, hypertension, hyperlipidemia, smoking status, and overweight/obese status with onset of incident depression. Adjustment covariates were race, enrollment wave, baseline age, physical activity, and heavy alcohol use. Results: The analysis included 44,175 person-years of follow-up. Among participants depression-free until age 65, vascular risk-factor burden after age 65 (Hazard Ratio, [HR]: 2.13, 95% Confidence Interval, [CI]: 1.17, 3.90) was associated with incident depression risk after age 65. The magnitude of vascular risk-factor burden after age 65 on depression risk after age 65 is comparable to the effect of 8.2 additional years of age. Diabetes (HR: 2.79, 95% CI: 1.25, 6.26), hypertension (HR: 2.72, 95% CI: 1.52, 4.88), and hyperlipidemia (HR: 1.88, 95% CI: 1.05, 3.35) before age 65 were associated with incident depression risk after age 65. Men diagnosed with diabetes after age 65 had 2.87 times the risk of incident depression after age 65 (95% CI: 1.24, 6.62). Limitations: Our findings are restricted to male former medical students, which may affect study generalizability. Conclusions: Results support the vascular depression hypothesis. Depression screening in older adults with vascular risk-factor burden may provide an avenue for prevention of late-onset depression.