CD4 + T-lymphocyte counts are used to assess CD4 + decline and the stage of human immunodeficiency virus (HIV) progression in HIV-infected patients. Clinical observation suggests that HIV progress more rapid in females than males. Of the original 5000 HIV-infected population of Western New York HIV/AIDS, Referral Center at Erie County Medical Center (ECMC), 1422 participated in the cohort study. We identified 333 HIV-infected patients with CD4 + T-cell-counts ≥ 500/µƖ, among them 178 met the inclusion criteria for the 10-year study. Females had higher mode (600 vs. 540) and mean (741.9 vs. 712.2) CD4 + counts than males at baseline. However, CD4 + declined faster among females in a shorter time than males (234.5 vs. 158.6, P < 0.004), with rapid HIV progression. Univariate analyses determined that females had a 40% higher risk for CD4 + decline than males. The bivariate analyses specified CD4 + decline remained greater in females than males. Multivariate analyses which employed Cox's proportional Hazard-Model to adjust for numerous variables simultaneously identified women had almost twice the risk for CD4 + decline and rapid HIV progression than males (RR = 1.93; 95%CI 1.24, 2.99). Although the biological mechanism remains unknown, findings suggest gender differences in CD4 + decline, with a higher risk of rapid HIV progression and shorter longevity in females.