Introduction: Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnaeipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnaeipran could modify the status of conditioned pain modulation (CPM) inpatients suffering from fibromyalgia. Design and setting: Randomized, double-blind controlled trial. Subjects and methods: Women with fibromyalgia received milnaeipran 100 mg or placebo. Tlie primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnaeipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance. Results: Fifty-four women with fibromyalgia (46.7 +/- 10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion. CPM was dysfunctional (CPM30=-0.5 +/- 1.9), and global pain was 6.5 +/- 1.8. After treatment, there was a nonsignificant CPM difference between milnaeipran and placebo (CPM30=-0.46 +/- 1 .22 vs -0.69 +/- 1.43. respectively, p=0.55) and 18.8% vs 6.3 % (p=0.085) patients did reactivate CPM alter milnacipran vs placebo. Initial CPM was not a predictor of milnaeipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups. Conclusion: Milnaeipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnaeipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients.