The effect of nefazodone (N) on platelet aggregability (PA) to an epinephrine (E) agonist, plasma (E) and plasma norepinephrine (NE) to an orthostatic challenge was examined in 8 healthy volunteers. Subjects were examined before and after 200 mg BID of N for 8 days. Six of 8 subjects completed the protocol. Three were orthostatic (diastolic blood pressure drop >5 mm Hg or pulse increase >20 beats per minute) after standing 5 minutes and 3 were not. For the entire group (n=6), N did not change mean NE (pg/ml), E (pg/ml), or PA (%) but subjects orthostatic (ortho) upon standing had increased mean NE, E, and PA while those subjects not orthostatic (n=3) had decreased NE, E, and PA. NE E PA before after before after before after All n=6 389 496 247 318 33.5 32.1 Ortho 267 660 92 466 29.7 46.7 Not-ortho 512 332 402 170 37.3 17.7 The a blocking properties of N may have caused vasodilation, increased NE and E, with resultant increase in PA in the orthostatic subjects. In the non-orthostatic subjects platelet 5HT2 blockade by N and/or decreased E could explain the decreased PA. Additional studies are clearly needed to further define the hemodynamic effects of N.