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HIV-1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression.To assess racial and gender differences in HIV-1 RNA levels and CD4+ lymphocyte decline.A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States.In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral therapy were included. Women were more likely to be nonwhite, to have a history of injection drug use, and to have HIV-associated symptoms. After adjustment for differences in measurement method, baseline CD4+ cell count, age, and clinical symptoms, HIV-1 RNA levels were 32% to 50% lower in women than in men at CD4+ counts >200 cells/mm3(p < .001) but not at CD4+ cell counts <200 cells/mm3. HIV-1 RNA levels were also 41% lower in nonwhites than in whites (p < .001) and 21% lower in persons reporting a prior history of injection drug use (p < .001). Women had more rapid declines in CD4+ cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4 cell counts than whites (difference of 39 cells/year).Both race and gender influence the values of HIV-1 RNA and the rate of HIV-1 disease progression as indicated by decline in CD4 cell counts over time. These effects could provide clues regarding the factors that influence HIV-disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics.