Objective: To evaluate the efficacy and tolerability of adjunctive ziprasidone in subjects with treatment-resistant major depressive disorder (DSM-IV criteria) without psychotic features. Method: Subjects not responding to selective serotonin reuptake inhibitor (SSRI) monotherapy during a 6-week open-label trial were randomly assigned to continue monotherapy or receive adjunctive ziprasidone for 8 weeks in 1 of 3 groups: sertraline 100 to 200 mg/day, sertraline 100 to 200 mg/day plus ziprasidone 80 mg/day, or sertraline 100 to 200 mg/day plus ziprasidone 160 mg/day. The trial was conducted from May 2001 to October 2002. Ziprasidone was administered twice daily. Primary efficacy measure was the least squares mean change on the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline of the 8-week phase to study end point. Results: In total, 64 subjects were randomly assigned to sertraline monotherapy (N = 21), sertraline plus ziprasidone 80 mg/day (N = 23), or sertraline plus ziprasidone 160 mg/day (N = 20). Mean ± SE improvement in MADRS total score on adjunctive ziprasidone 80 mg/day and ziprasidone 160 mg/day versus monotherapy, respectively, was -5.98 ± 1.87 and -8.27 ± 2.17 versus -4.45 ± 2.03 (p = NS). Response rates for these groups were 19% (N = 4), 32% (N = 6), and 10% (N = 2), respectively (p = NS). No clinically significant changes were reported on physical examination, laboratory tests, or electrocardiogram on either adjunctive dose of ziprasidone. Conclusions: In this preliminary study of antidepressant-resistant subjects with major depression, adjunctive ziprasidone was associated with greater clinical effect than was continued sertraline monotherapy and was generally well tolerated. These data suggest that further controlled study of ziprasidone in treatment-resistant depression is warranted.