Whether fluoxetine (FX) is effective in the treatment of anxious depression is still debated. In the present study, after one week of placebo (single blind), 142 outpatients affected by major depression with relevant anxiety and agitation were randomly assigned (double blind) to either FX (20 mg/day) (n. 67) or amitriptyline (AM) (daily dose: 115+/-39.2mg) (n.75) for a period of 10 weeks. Between groups, the mean score of Hamilton Rating Scale for Depression (HRSD) was significantly different only after 3 weeks of treatment (AM 14.7+/-5.7 vs FX 17.3+/-6.2 (p = 0.02), whereas at the end of the trial it was similar (AM 8.15+/-6.9; FX 8.96+/-6.6). At each visit, no significant difference between groups was found regarding the scores of the HRSD items "psychic anxiety", "somatic anxiety", "agitation". Furthermore, the FIX treatment did not increase the scores of the items "suicide", "psychic anxiety", "somatic anxiety", "agitation" and "insomnia". These findings suggest that patients affected by major depression with anxiety and/or agitation were effectively and safely treated with FX without increasing risks.