BACKGROUND: Cellulose sulfate (CS) is an antimicrobial and contraceptive agent. We assessed its safety when used alone or with the diaphragm in Harare, Zimbabwe. STUDY DESIGN: This was a randomized controlled safety trial with three arms: diaphragm with 6% CS gel vs. diaphragm with KY gel vs. CS gel alone. Participants were instructed to use their study products before every sex act for a period of 6 months. Safety end points were assessed monthly by questionnaires and urinanalysis and bimonthly by clinical examinations, colposcopy, wet mounts and gram stains. RESULTS: One hundred nineteen monogamous women were enrolled (28% HIV+) and 105 (88%) completed the study. No urinary tract infections were diagnosed during the study; 81.4% women had symptoms and/or signs of genital irritation considered at least possibly related to the gel or device, and 41.5% had changes in vaginal flora. There were no statistically significant differences between treatment groups in safety end points. All six women with deep epithelial disruption were diaphragm users, and all such findings were on the external genitalia. Of those, 4 had herpetic ulcers which were unrelated to products use. CONCLUSIONS: Cellulose sulfate appeared safe when used for 6 months alone or with a diaphragm.