Background: Studies of pindolol augmentation of antidepressants in major depressive disorder have produced mixed results, and data in treatment-resistant patients are limited. Here, we report on a double-blind, randomized, controlled 6-week study of pindolol augmentation of selective serotonin reuptake inhibitors (SSRIs) in depressed outpatients resistant to SSRI monotherapy. Method: Forty-two outpatients with DSM-IV major depressive disorder who had an insufficient response to an adequate trial of an SSRI (fluoxetine, paroxetine, or sertraline) were randomly assigned to pindolol, 2.5 mg t.i.d., or sham augmentation, in addition to continued SSRI administration. For separate analysis, the control group underwent a single-blinded switch to pindolol, 2.5 mg t.i.d., from week 4 through week 6, while the active group was continued on pindolol augmentation (hemi-crossover design). Change in Hamilton Rating Scale for Depression (HAM-D) score from baseline to the end of week 3 was the primary outcome measure. Data were gathered from February 1994 to August 1998. Results: Thirty-eight patients completed at least 1 week on protocol, with 21 and 17 randomly assigned to the pindolol and control groups, respectively. After 3 weeks on protocol, partial response rates (i.e., minimum 50% decrease from baseline in HAM-D score and maximum absolute score of 15) for the pindolol (19% [4/21]) and control (24% [4/17]) groups were comparable. At 3 weeks, the pindolol and control groups demonstrated mean ± SD decreases in HAM-D scores of 6.5 ± 9.8 and 9.7 ± 7.2, respectively. There were no significant differences in antidepressant response or side effects between the 2 groups. Conclusion: These results do not support the efficacy of pindolol in augmenting clinical response to SSRIs in treatment-resistant depressed patients.