Studies of human immunodeficiency virus (HIV) infection often compare values from HIV-uninfected controls, including CD4 and CD8 lymphocyte counts. Nonetheless, little is known regarding factors associated with CD4 and CD8 cell numbers in HIV-uninfected individuals. To ascertain potential factors associated with differences in CD4 and CD8 cells among HIV negative women, we studied these cells in a group of 953 women, enrolled as HIV-negative comparators in the Women's Interagency HIV Study. Using standard techniques, we measured CD4 and CD8 cells obtained during study-related visits every six months through visit 20 (maximum of 9.5 years). Results were correlated with demographic and behavioral factors, and data were analyzed using a multiple linear regression approach with generalized estimating equations. At baseline, the median age was 32.4 years, body mass index (BMI) was 26.4 kg/m(2), CD4 cell count was 1010 (range 214-2705)/microL, and CD8 cell count was 542 (range 72-2448)/microL. African-Americans comprised 54%, 24% were Hispanic, and 19% were Caucasian. In multivariate analysis, increasing age (p = 0.0006), increasing BMI (p = 0.001), and current smoking status (p = 0.03) were independent predictors of higher CD4 counts. Multivariate analyses of CD8 cells revealed that lower age (p = 0.001), higher BMI (p = 0.03), Hispanic race/ethnicity (p = 0.01); current smoking (p = 0.006), injection drug use (p = 0.02), and Hepatitis C infection (p = 0.01) were independent predictors of higher CD8 cell counts. Multiple demographic and behavioral factors may influence CD4 and CD8 counts in HIV negative women. These factors must be considered in future analyses comparing lymphocyte subsets in HIV positive and negative women.