The effects of therapy with the tricyclic antidepressant protriptyline were studied in 12 patients with hypersomnolence and moderately severe sleep apnea. After treatment there was no significant change in the duration or frequency of sleep-disordered breathing (SDB) during non-REM sleep, but there was an alteration in the breathing pattern characterized by a decrease in the amount of apnea during SDB events. Apnea, as a percent of disordered breathing time, fell from 60.4 +/- 27.2% to 35.5 +/- 26.7% (p less than 0.01) and was accompanied by a reduction in the peak fall in oxygen saturation from 16.2 +/- 6.2% to 9.2 +/- 4.7% (p less than 0.01). During REM sleep there was no change in the pattern, duration, or frequency of SDB, or reduction in the peak fall in oxygen saturation. However, there was a reduction in the amount of Stage REM sleep, thereby reducing the more severe SDB events (p less than 0.01) and further improving nocturnal oxygenation. In 10 of 12 patients, there was subjective improvement in daytime hypersomnolence, which was associated with an increase in median sleep onset time from 3.3 +/- 2.2 to 5.1 +/- 2.1 min (p less than 0.01). Although all patients developed mild side effects from the anticholinergic properties of protriptyline manifested by a dry mouth, 4 patients noted additional side effects including urinary hesitancy, mild constipation, and difficulty in maintaining an erection. One patient developed intolerable constipation that necessitated discontinuation of the drug. We conclude that protriptyline reduced daytime hypersomnolence and altered the pattern of SDB, thus improving gas exchange and oxygenation during sleep. Therefore, in selected patients with moderately severe obstructive sleep apnea, therapy with protriptyline is an alternative to surgical treatment with a tracheostomy.