Vaginal candidiasis (VC) is a common concern for women living with HIV infection. The authors evaluated the effectiveness of two self-care approaches to prophylaxis of VC among HIV-infected women, weekly intravaginal application of Lactobacillus acidophilus or weekly intravaginal application of clotrimazole tablets, in a randomized, double-blind, placebo-controlled trial. VC was defined as a vaginal swab positive for Candida species in the presence of signs/symptoms of vaginitis and the absence of a diagnosis of Trichomonas vaginalis or bacterial vaginosis. Thirty-four episodes of VC occurred among 164 women followed for a median of 21 months. The relative risk of experiencing an episode of VC was 0.4 (95% CI = 0.2, 0.9) in the clotrimazole arm and 0.5 (95% CI = 0.2, 1.1) in the Lactobacillus acidophilus arm. The estimated median time to first episode VC was longer for clotrimazole (p = .03, log rank test) and Lactobacillus acidophilus (p = .09, log rank test) compared with placebo. Vaginal yeast infections can be prevented with local therapy. Education about self-care for prophylaxis of VC should be offered to HIV-infected women.