OBJECTIVES: This study aimed to compare the tolerability and efficacy of two different titrations of paroxetine (slow and standard) in a population of cancer patients with depression. METHODS: This randomized open trial included 30 cancer patients with depression (major depressive disorder, dysthymic disorder, or adjustment disorder with depressed mood) and aimed to compare the safety of slow up-titration (arm A) versus standard up-titration (arm B) of paroxetine chlorhydrate. In both arms, the maximum final dose was 20 mg/day. Patients were evaluated at baseline and after 2, 4, and 8 weeks with rating scales for depression and anxiety (MADRS, HADS, HAM-A, CGI), quality of life (EORTC-QLQ-30), and side effects (DOTES, SIDE). RESULTS: Thirty consecutive cancer patients (F = 21; M = 9) meeting DSM-IV TR criteria for mood disorders (MD) were enrolled in the study and randomly assigned to slow or standard paroxetine titration. Both treatment groups showed a significant mood improvement (change in MADRS total score) from baseline to end point (arm A-F(2,18) = 33.68 p < 0.001; arm B-F(2,12) = 6.97 p < 0.005). A significantly higher rate of patients in arm A compared with arm B showed no side effects after 2 weeks (40% vs. 6.7%, respectively). A multinomial logistic regression confirmed such differences between arms (chi square = 20.89 p = 0.004). The self-evaluating scale (SIDE) confirmed this difference: 60% of subjects in arm B perceived side effects compared to only 11.1% of patients in arm A. CONCLUSIONS: The results of this study suggest that slow paroxetine up-titration is better tolerated and at least as effective as the standard paroxetine up-titration in cancer patients with depression.