Context: The prevalence of depression in later life increases with plasma total homocysteine concentration (tHcy). High tHcy accounts for about 15% of prevalent cases, but observational studies are prone to confounding and bias. Genetic association studies are not prone to the same sources of error and offer an opportunity to explore the consistency and external validity of this association.Objective: To determine if tHcy is causally related to depression in later life.Design: Cross-sectional study (Health in Men Study), systematic review, and meta-analysis.Patients: Community sample of 3752 men aged 70 years or older (Health in Men Study).Main Outcome Measures: Fifteen-Item Geriatric Depression Scale and self-reported past or current treatment for depression (Health in Men Study).Results: In the Health in Men Study, the odds ratio (OR) of prevalent depression increased 4% (OR, 1.04; 95% confidence interval [CI], 1.02-1.05) with every unit increase of tHcy (micromoles per liter). The tHcy was 0.19 mg/L higher among participants with the MTHFR C677T TT genotype compared with the CC genotype. The meta-analysis showed that older adults with high tHcy had increased risk of depression (OR, 1.70; 95% CI, 1.38-2.08) and TT carriers were 22% more likely than CC carriers to have current depression or a history of depression (OR, 1.22; 95% CI, 1.01-1.47).Conclusions: The triangular association between the MTHFR genotype, tHcy, and depression implies that higher concentrations of tHcy increase the risk of depression and that lowering tHcy by 0.19 mg/L could reduce the odds of depression by about 20%. Confirmatory data from sufficiently powered randomized trials of homocysteine-lowering therapy are now required to test if the relationship between tHcy and depression is truly causal.