BACKGROUND: To compare the success rate and cost effectiveness (from the perspective of the health care provider) of ciprofloxacin (C) and trimethoprim/sulfamethoxazole (TMP/SMX) in the ambulatory treatment of women with acute uncomplicated pyelonephritis (AUPN). METHODS: A randomized double blind study was performed on women presenting to the emergency room with symptoms of AUPN. Treatment regimens consisted of either: C (500mg) twice daily or TMP/SMX (160mg/800mg) twice daily. Duration of treatment was 14 days. The data necessary to calculate success rates and direct medical costs were collected. RESULTS: A total of 89 patients were randomized and included in the cost effectiveness analysis. 36 patients (C:19; TMP/SMX:17) were excluded from the success rate analysis for the following reasons: 2 due to renal abnormalities (C:11; TMP/SMX:1), 3 due to failed urine cultures (C:12; TMP/SMX:1), 9 due to resistance to TMP/SMX (C:5; TMP/SMX:4), 16 due to negative urine cultures (C:7; TMP/SMX:9) and 6 due to lost to follow up (C:4; TMP/SMX:2). 53 Evaluable patients remained (C:26; TMP/SMX:27). Treatment success was defined as a negative urine culture and absence of symptoms at the time of the follow up visit. Overall success rate: C:22/26; TMP/SMX:16/27 (p=0.0405). Direct medical costs: C:278.39$; TMP/SMX:546.15$ Canadian (p=0.0048). CONCLUSION: C produces less side effects and has a higher cure rate than TMP/SMX. As a result, and despite its higher acquisition cost, C is more cost effective then TMP/SMX in the ambulatory treatment of AUPN in women.