To examine the tolerability and efficacy of duloxetine in patients with suspected sphincter of Oddi dysfunction (SOD). An open-label, single-center, 12-week trial of duloxetine 60 mg once daily was conducted in 20 patients with suspected SOD. All patients were evaluated by expert pancreato-biliary specialists. The primary outcome measure was a Patient Global Impression of Change (PGIC) scale. Secondary measures included the pain burden, assessed by the Recurrent Abdominal Pain Intensity and Disability scale, the Short-Form Health Survey, and the Hospital Anxiety and Depression Scale. A positive clinical response was defined as a PGIC score of much or very much improved at 3 months and was estimated using a two-sided 90 % confidence interval. The primary outcome was analyzed using a one-sample binomial test at a significance level of 0.10. Of the 20 screened patients, 18 were enrolled; 14 completed at least one post-baseline evaluation; and 10 patients completed the third month endpoint visit. Patients missing the third month visit were considered non-responders for the primary outcome. Response rates were 90 % for study completers (n = 10; 90 % CI 74–100; p = 0.02) and 64 % for patients who completed at least one post-baseline evaluation (n = 14; 90 % CI 43–85; p = 0.42). Seven patients did not complete the study due to adverse events (mostly fatigue and nausea). Duloxetine showed an indication of efficacy in the treatment of pain in patients with suspected SOD, but adverse events limited its use. These preliminary, open-label results justify definitive placebo-controlled trials.