The clinical polysomnographic (PSG) reports of 2,650 consecutive adults studied during 41 months were reviewed retrospectively to identify all patients treated with fluoxetine or tricyclic antidepressants. The PSG reports of four other adult groups were also reviewed: periodic limb movement (PLM) disorder (n = 28); sleep terror/sleepwalking (ST/SW) (n = 54); rapid eye movement (REM) sleep behavior disorder (RBD) (n = 70); patients with clinically unremarkable sleep during two consecutive PSG studies (n = 30). Standard PSG recording and scoring methods were employed. A total of 1.5% (n = 41) and 2.0% (n = 52) of patients were receiving fluoxetine or tricyclics (amitriptyline or nortriptyline, n = 31; imipramine or desipramine, n = 16; protriptyline or trimipramine, n = 5). A selective association between fluoxetine and extensive, prominent eye movements in nonrapid eye movement (NREM) sleep was detected, utilizing Fisher's exact one-tailed statistic (p less than 0.00001 for each comparison). The detection rates were fluoxetine, 48.8% (20/41); tricyclics, 5.8% (3/52); RBD, 4.3% (3/70); objectively normal sleepers, 3.3% (1/30); PLM, ST/SW, 0% (0/82). These groups had similar mean ages (31.5-45.4 years) and gender distributions (50.0-60.7% male), apart from RBD. The effect of fluoxetine, a potent and specific serotonin reuptake inhibitor, on NREM eye movements is postulated to derive from potentiation of serotonergic neurons that inhibit brainstem "omnipause neurons", which, in turn, inhibit saccadic eye movements, thus resulting in disinhibited release of saccades. In addition, a 31-year-old man with obsessive-compulsive disorder developed RBD soon after starting fluoxetine therapy, which persisted at PSG study 19 months after fluoxetine discontinuation.