BACKGROUND ACIDFORM is a microbicidal and contraceptive candidate with strong buffering capacity. METHODS This was a Phase I blinded, randomized and crossover clinical study on two products, ACIDFORM and a commercial nonoxynol-9 (N-9) product (2%), evaluating their vaginal safety in 20 couples aged between 19 and 45 years. The women had regular menses, underwent previous tubal ligation, were not breast-feeding, had no vaginal sign and symptom and were in a stable partnership; both partners had no previous STI. Colposcopy, vaginal microbiology, inflammation markers and subject complaints were studied after coitus. Women were randomly assigned sequentially to receive ACIDFORM 0-30 min (0-30 min before intercourse), ACIDFORM 8-10 h (8-10 h before intercourse) or N-9 0-30 min after a control cycle. RESULTS Mild/moderate vulvar irritation was observed in five postcoital test colposcopies, burning and pruritus were reported in six treated cycles and non-irritation-related symptoms were found in five cycles with different treatments. No difference in vaginal pH, Nugent scores, H2O2-producing lactobacillus or leukocytes and interleukin 6 in the cervicovaginal lavage was found between the treatment and control cycles. CONCLUSIONS ACIDFORM appears to be safe for clinical use once a day. There is a potential spermicidal-microbicidal role for ACIDFORM as a vaginal flora helper or as a vehicle for products, except N-9.