This meta-analysis examined efficacy and tolerability data from 39 randomized, double-blind, parallel-group studies comparing paroxetine (n = 1924) with clomipramine (n = 141) or other tricyclic antidepressants (TCAs; n = 1693) in the treatment of major depression. Paroxetine had comparable antidepressant efficacy to TCAs, including clomipramine, as assessed by response rates based on a < or = 50% reduction in Hamilton Rating Scale for Depression (HAMD) total score (58-66%) and a HAMD total score < or = 8 (38-48%) at endpoint, and absolute improvements in HAMD total score (mean change 12.3-14.5). Absolute improvements in HAMD anxiety factor scores were similar between paroxetine and clomipramine (mean change 2.3 versus 2.4, P = 0.566), but paroxetine was statistically significantly more effective on this measure than other TCAs (mean change 2.3 versus 2.1, P = 0.028). The proportion of patients who experienced adverse events with > 1% incidence was statistically significantly lower with paroxetine than with clomipramine (64% versus 77%, P = 0.02) or other TCAs (64% versus 71%, P < 0.001). The incidence of patient withdrawals due to adverse events was also statistically significantly lower with paroxetine than with clomipramine (17% versus 27%, P = 0.014), but an advantage seen for paroxetine over other TCAs (17% versus 20%, P = 0.130) did not reach statistical significance. These findings demonstrate that paroxetine has comparable efficacy to and better tolerability than TCAs, including clomipramine, and is therefore an appropriate treatment strategy for depression, particularly in the common clinical situation where concomitant anxiety symptoms are present.