Background. Whether human immunodeficiency virus (HIV) seroconverters have been presenting with progressively lower CD4 cell counts over the course of the HIV epidemic is controversial. Additional data on whether HIV might have become more virulent on a population level (measured by post-seroconversion CD4 cell counts) may provide important insights regarding HIV pathogenesis. Methods. To determine whether post-seroconversion CD4 cell counts have changed over time, we evaluated 2174 HIV seroconverters as part of a large cohort study during the period 1985-2007. Participants were documented antiretroviral-naive HIV seroconverters who had a CD4 cell count measured within 6 months after receiving a diagnosis of HIV infection. Multiple linear regression models were used to assess trends in initial CD4 cell counts. Results. The mean initial CD4 cell count decreased during the study period from 632 cells/mm3 in 1985-1990 to 553 cells/mm3 in 1991-1995, 493 cells/mm3 in 1996-2001, and 514 cells/mm3 in 2002-2007. During those periods, the percentages of seroconverters with an initial CD4 cell count <350 cells/mm3 were 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean decrease in CD4 cell count from 1985-1990 was 65 cells/mm3 in 1991-1995 (P< .001), 107 cells/mm3 in 1996-2001 (P< .001), and 102 cells/mm3 in 2002-2007 (P< .001). Similar trends occurred with regard to CD4 cell percentage and total lymphocyte count. Similar decreases in initial CD4 cell counts were observed among African American and white persons during the epidemic. Discussion. A significant decrease in initial CD4 cell counts among HIV seroconverters in the United States has occurred during the HIV epidemic. These data provide an important clinical correlate to suggestions that HIV may have adapted to the host, resulting in a more virulent infection.