Praneem polyherbal formulations containing purified extracts of Azadirachta indica (neem tree) have shown activity against HIV and sexually transmitted disease pathogens in studies in vitro. The product also has contraceptive properties. This has prompted its development as a possible microbicide. We evaluated the safety of Praneem polyherbal tablet use among HIV-uninfected women. Twenty eligible women were enrolled in a Phase I open-label study requiring 14 days of consecutive intravaginal use of Praneem polyherbal tablets. Nine (45%) participants experienced 17 episodes of genital irritation. Transient genital itching was reported by eight (40%) participants, burning micturation by two (10%) and lower abdominal pain, genital burning and intermenstrual spotting by one (5%) each. On colposcopy, petechial haemorrhage was observed in two participants, one on day 7 and the other on day 14, and both were resolved without any treatment. There were no serious adverse events. Praneem polyherbal tablets were found to be safe for once daily intravaginal use for 14 consecutive days in sexually active HIV-uninfected women and a Phase II study may be taken up as a priority.