In a preclinical study we found fluoxetine alone to induce a serotonin-mediated, dose-dependent antinociceptive effect in the mouse hot plate assay. In the present study we evaluated the clinical implication of these findings, comparing the efficacy of fluoxetine with that of amitriptyline for musculo-skeletal pain. Forty non-depressed patients, suffering from low back pain and whiplash associated cervical pain were enrolled in a randomized, six-week, "blind-rater" study, comparing the analgesic effect of amitriptyline (50-75 mgs/day) with that of fluoxetine (20 mgs/day). Twenty patients were randomly assigned to the amitriptyline group, and twenty to the fluoxetine group. Visual analogue and verbal rating scales were used for the assessment of pain intensity and pain relief. Thirty-five patients concluded the study. Moderate or good relief of pain was reported by 14 of the 17 patients (82%) in the amitriptyline group, and by 14 of the 18 patients (77%) in the fluoxetine group. The difference in responses between amitriptyline and fluoxetine was not statistically significant. In our study, fluoxetine relieved low back pain and whiplash associated cervical pain with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the tricyclic antidepressants' side effects.