Abstract: Sleep electroencephalographic activity, circadian rhythms in motor activity and rectal temperature, and clinical state were monitored longitudinally in four affectively ill patients (two depressed, one manic, and one rapidly cycling between depression and mania) who lived in isolation from external time cues (zeitgebers) for 3 to 4 weeks. In these conditions it was possible to observe the intrinsic or free-running behavior of circadian pacemakers and thereby to test several hypotheses about the role of sleep and circadian rhythms in the pathogenesis of depression. No hypothesis was consistently supported by the results. We found that the intrinsic rhythm of a circadian pacemaker appeared to free-run with an abnormally fast frequency in one patient. No patient remained stably depressed during temporal isolation. Our experience suggests that this type of study can be carried out safely with appropriate precautions. Temporal isolation is a means to test decisively predictions of several chronobiological hypotheses about affective illness and should be applied to additional patients.