BACKGROUND: There is an association between higher white blood cell counts and all-cause and cardiovascular disease (CVD) mortality. However, little is known about the prognostic significance of circulating lymphocyte and lymphocyte subset numbers. AIMS: The present study examined the association between T-, CD4-, CD8- and B-cell numbers, and the CD4:CD8 ratio, and all-cause and CVD mortality. METHODS: Lymphocyte and lymphocyte subset numbers were measured by flow cytometry in a cohort of 4256 male middle-aged Vietnam-era US veterans. Mortality was tracked for 15 years and cause of death was determined from death certificates. RESULTS: In fully adjusted survival analyses, high circulating T-cells numbers were associated with increased risk of both all-cause [hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.15-2.66] and cardiovascular (HR = 3.57, 95% CI 1.53-8.33) mortality. The former association appeared to reflect an effect for high CD8-cells numbers, the latter an effect for high CD4-cell numbers. For all-cause mortality, a high CD4:CD8 ratio was protective (HR = 0.58, 95% CI 0.41-0.81). Cardiovascular mortality was also predicted by high B-cells numbers (HR = 1.87, 95% CI 1.10-3.17). CONCLUSION: Circulating lymphocyte and lymphocyte subset numbers may have substantial prognostic significance for both all-cause and CVD mortality.