The objective of this study was to compare the tolerability of Advantage 24 to two other spermicides containing non-oxynol-9 (N-9). These spermicides were Today Sponge (Sponge) and Conceptrol. In order to examine the incidence of complaints and the clinical observation of vaginal ulceration and irritation of the three spermicides, a randomized, open label, three period cross-over trial was conducted. Thirty-three women, ages 18-45, with a normal vaginal environment based on physical exam, Pap smear, vaginal wet prep, colposcopy, and serum N-9 were randomized into four treatment groups. Each treatment was for seven consecutive days with a 21-day washout. Data obtained were studied by one-way analysis of variance, chi-square, and Kruskal-Wallis test. No vulvar or vaginal abnormality was observed from either spermicide. Subjects had fewer and less severe cervical lesions by colposcopy during treatment with Advantage 24 than with Conceptrol or Sponge (p < 0.01). Comparison of the incidence of abnormal gynecological findings, serum N-9 levels, and the incidence of adverse events before and after treatment with the three study drugs indicate that most subjects had normal examinations pre- and post-treatment. Pap smear and colposcopy changes from normal to abnormal accounted for about 50% of all gynecological findings during the Conceptrol and Sponge treatments, but less than 20% during treatment with Advantage 24. All serum N-9 levels were below the level of detection (< 1.9 microgram/ml). Advantage 24 is better tolerated than Conceptrol or the Sponge. Furthermore, the cervical mucosa appears to be less resilient to spermicides than vulvo-vaginal mucosa.