The association of xerostomia and salivary gland hypofunction with HIV infection has been established for men but not for women. We investigated the prevalence of these conditions in a national cohort (n = 733) of HIV-positive and at-risk HIV-negative women. Participants in this prospective cross-sectional study were recruited from the Women's Interagency HIV Study (WIHS) at five outpatient USA clinics. Xerostomia was assessed based on "yes" responses to a dry-mouth questionnaire. Samples of unstimulated whole and chewing-stimulated whole saliva were collected under standardized conditions. The major salivary glands were also evaluated clinically. The prevalence of dry-mouth complaint, the absence of saliva upon palpation, and zero unstimulated whole saliva (flow rate = 0 mL/min) were significantly (p = 0.001) higher in HIV-positive women. Adjusted odds of zero unstimulated whole saliva were significantly (p = 0.02) higher in HIV-positive women vs. HIV-negative women (OR = 2.86; 95% CI, 1.23 to 6.63). Significant (p = 0.03) univariate association was found between zero unstimulated whole saliva and CD4 counts. Adjusted odds of zero unstimulated whole saliva were significantly (p = 0.02) higher for HIV-positive women with CD4 < 200 compared with those with CD4 > 500 (OR = 2.61; 95% CI, 1.17 to 5.85). Chewing-stimulated flow rates were not significantly different between seropositive and seronegative women. The prevalence of xerostomia and salivary gland hypofunction appears to be significantly higher in HIV-positive women relative to a comparable group of at-risk seronegative women. Immunosuppression levels measured by CD4 cell counts are significantly associated with xerostomia and salivary gland hypofunction in a population of HIV-positive women.