Background: This general practice-based case-control study tested the association between cerebrovascular risk factors (CVRFs) and the development of later-life depression by focusing on the impact of exposure duration to CVRFs and the modifying influence of age at depression onset. Methods: Cases were 286 patients aged ≥ 50 years with a first diagnosis of depression at age ≥ 50 years. Nondepressed controls (N = 832) were individually matched for age, gender and practice. CVRF diagnoses (hypertension, diabetes mellitus, cardiovascular conditions) prior to depression were determined. Analyses controlled for education, somatic and nondepressive psychiatric disease. Results: No CVRF variable examined was significantly associated with subsequent depression in the total sample. An unexpected impact of age at onset of depression was observed: the odds ratio associated with having any CVRF was smaller for patients with age at onset ≥ 70 years than for patients with onset between ages 50-59 years (p = .002) and 60-69 years (p = .067). Subsequent analyses excluding patients with onset at age ≥ 70 years revealed that CVRF variables, including long-term exposure to CVRFs, significantly increased the odds of subsequent depression with onset between ages 50 and 69 years. Limitations: Reliance on GPs' records of morbidity may have resulted in bias towards underestimation in patients with depression onset at age ≥ 70 years. Conclusions: Our findings suggest that CVRFs play a relevant role in the development of depression with onset between ages 50 and 69 years, but no evidence was found that they contribute to the occurrence of depression with onset at age ≥ 70 years. Replication is warranted to exclude the possibility of bias.