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The upregulation of HIV-1 co-receptor expression during certain clinical settings may explain the predisposition of individuals to enhanced HIV-1 acquisition. We sought to determine the effect of estrogen and progesterone on the HIV-1 coreceptors, CCR5 and CXCR4. Co-receptor expression on CD3- and CD14-positive cells obtained systemically and locally (genital tissue in women) was determined in men, pre- and post-menopausal women, pregnant women in each trimester and in labor. CCR5 on both CD3- and CD14-positive cells was highest in pregnant women, and increased as gestation advanced (P < .01 and P < .001, respectively). Progesterone levels were significantly associated with CCR5 expression on PBMCs (P < .03 for CD3-positive, and P < .002 for CD14-positive cells) and from cells isolated from tissue (P < .001).CCR5 mRNA expression correlated with the cell surface marker expression from blood and tissue. These findings suggest that pregnancy and other high progesterone states may predispose women to HIV-1 acquisition. [ABSTRACT FROM AUTHOR]