Lower circulating homoarginine concentrations have been associated with morbidity and mortality in patients with established cardiovascular disease (CVD). We assayed plasma homoarginine concentrations in 3331 Framingham Offspring Study participants attending examination cycle six (mean age 58.6 years, 53% women). We evaluated correlates of plasma homoarginine and related homoarginine to incident CVD and death. We also classified participants as having higher (upper quartile) versus lower (lower three quartiles) homoarginine and previously assayed asymmetric dimethylarginine (ADMA) concentrations, and created cross-classification groups. We observed 630 incident CVD events and 940 deaths during a median follow-up of 18 years. In multivariable regression analysis, homoarginine was associated positively with male sex, body mass index, anti-hypertensive medication use and systolic blood pressure, but inversely with age and smoking. Higher homoarginine levels were associated with a lower mortality risk (hazard ratio (HR) per SD increment, 0.83, 95% CI: 0.74–0.93) adjusting for standard CVD risk factors, and ADMA. Among the cross-classification groups, participants with higher homoarginine and lower ADMA had a lower mortality risk (HR, 0.81, 95% CI: 0.67–0.98) compared to those with low levels of both. Further studies are needed to dissect the mechanisms of the association of homoarginine and mortality over decades in the community.