The efficacy of the potent and selective unicyclic serotonin reuptake inhibitor, fluvoxamine, was evaluated in 38 consecutively admitted depressed patients judged refractory to standard antidepressants using operationalized criteria. Twenty-eight patients completed a single-blind protocol involving ≥2 weeks of placebo and 4–6 weeks of active fluvoxamine. Eight (29%) were judged responders to fluvoxamine alone, eight (29%) responded to lithium augmentation of fluvoxamine and two (7%) responded to fluvoxamine, lithium and perphenazine. These data suggest that selective and potent serotonin reuptake inhibitors may be effective in patients refractory to generally available antidepressant medications.