Objective: To assess the safety of dextrin sulphate (DS) gel compared to placebo gel in terms of local and systemic adverse events, and to determine the acceptability of dextrin sulphate gel. Design: A 4-week randomized trial of DS intra-vaginal gel, partially blinded, with placebo and observation control arms. Participants were randomized to use DS gel twice daily, placebo gel twice daily, DS gel pre-sex, or into an observation only arm. Methods: Sexually active women were recruited from post natal and HIV clinics at Nsambya Hospital, Kampala, Uganda. Screening, enrolment and follow-up visits took place every 1 or 2 weeks over an 8-week period and consisted of questionnaire interviews, colposcopy examinations, sexually transmitted infection screen and routine laboratory testing. Results: Out of a total of 172 women screened, 109 were randomized to use DS gel twice daily (65 women), placebo gel twice daily (15 women), DS gel pre-sex (nine women) or into an observation only arm (20 women). Two individuals had abnormal colposcopy findings in the DS twice daily gel use arm. Vaginal bleeding was reported as frequently by participants in the active gel arm as by participants in the placebo and observation only arms. No clinically significant difference was observed between arms in terms of vaginal flora, Candida, haemoglobin, white cell count, platelets, thrombin time, activated partial thromboplastin time, creatinine and aspartate aminotransferase results after 4 weeks of gel use. DS gel appeared to be acceptable to over 95% of the users. Conclusions: Results show a satisfactory safety and acceptability profile of dextrin sulphate gel.