BACKGROUND: The notion that selective serotonin reuptake inhibitors (SSRIs) may be associated with higher relapse rates than other antidepressants during maintenance treatment (tachyphylaxis) has been discussed for years, but to date there is little or no empirical evidence confirming this phenomenon. In this study, we systematically assessed prior anti-depressant treatment history in a cohort of depressed patients who presented for outpatient psychiatric treatment. Rates of tachyphylaxis were compared in venlafaxine and tricyclic antidepressants (TCAs), which act as dual reuptake inhibitors, versus SSRIs. METHOD: 237 patients who presented for treatment at the Rhode Island Hospital Department of Psychiatry's outpatient practice and were diagnosed with DSM-IV major depressive disorder were interviewed with the semistructured Treatment Response to Antidepressant Questionnaire. This cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of tachyphylaxis as a function of antidepressant class were compared. RESULTS: Rates of tachyphylaxis were significantly lower (chi(2) = 6.77, df = 1, p = .01) with the dual reuptake inhibitors venlafaxine and TCAs (3 [3.7%] of 82) compared to rates of tachyphylaxis with SSRIs (46 [14.1%] of 326). CONCLUSION: These results provide preliminary evidence that dual reuptake inhibitors may incur lower rates of tachyphylaxis than SSRIs. By virtue of the retrospective and non-random design of the study, these results warrant confirmation.