BACKGROUND: Tricyclic antidepressants have similar efficacy and slightly lower tolerability than selective serotonin reuptake inhibitors (SSRIs). However, there are no systematic reviews assessing amitriptyline, the reference tricyclic drug, v. other tricyclics and SSRIs directly. AIMS: To review the tolerability and efficacy of amitriptyline in the management of depression. METHOD: A systematic review of randomised controlled trials (RCTs) comparing amitriptyline with other tricyclics/heterocyclics or with an SSRI. RESULTS: We reviewed 186 RCTs. The overall estimate of the efficacy of amitriptyline revealed a standardised mean difference of 0.147 (95% CI 0.05-0.243), significantly favouring amitriptyline. The overall OR for dropping out was 0.99 (95% CI 0.91-1.08) and that for side-effects was 0.62 (95% CI 0.54-0.70), favouring the control drugs. With drop-outs included as treatment failures, the estimate of the effectiveness of amitriptyline v. tricyclics/heterocyclics and SSRIs showed a 2.5% difference in the proportion of responders in favour of amitriptyline (number needed to treat 40, CI 21-694; OR 1.12 (95% CI 1.01-1.24)). CONCLUSIONS: Amitriptyline is less well tolerated than tricyclics/heterocyclics and SSRIs, but slightly more patients treated on it recover than on alternative antidepressants.