The aim of the study was to evaluate the relationship between age-dependent changes in total leukocyte count (TLC) and certain selected differential counts expressed as frequencies (granulocytes, band cells, eosinophils, lymphocytes, and monocytes) and longevity in physically healthy men and women aged 45+. Longitudinal data on cell counts from 142 subjects (68 men and 74 women; all aged 45-70 and examined for 25 years) were compared with cross-sectional data from 225 subjects (113 men and 112 women; this group was divided into four categories of average lifespan; i.e.: 53, 63, 68, and 76+ years of age). ANOVA, t-test, and regression analysis were employed. Secular changes in leukocyte count were controlled. Men had continuously higher TLC compared with women. Moreover, sex differences in patterns of changes with age were found. The longitudinal assessment revealed a U-shaped pattern of changes in TLC in men (y=0.0026x(2)-0.2866x+14.4374; R(2)=0.852) and women (y=0.0048x(2)-0.5386x+20.922; R(2)=0.938), whereas the cross-sectional comparison showed an inverted U-shaped pattern in men (y=-0.0021x(2)+0.2421x; R(2)=0.417) and women (y=-0.0017x(2)+0.2061x; R(2)=0.888). In general, the comparison of longitudinal and cross-sectional data on changes with age in TLC indicates that longevity favors individuals with lower yet normal TLC and this correlation is more pronounced in men. In conclusion, our findings are in line with previous longitudinal studies of aging and suggest that lower TLC within the normal range (4.0-10.0 × 10(3)μL(-1)) can be a useful predictor of longevity in physically healthy individuals.