Psychomotor performance related to driving and occupational skills was measured double-blind and cross-over in 9 healthy volunteers before and 1.5, 3 and 4.5 hr after intramuscular injection of oxycodone (0.13 mg/kg), oral diphenhydramine (100 mg) and placebo. The effects of oxycodone on performance peaked at 1.5 hr when it prolonged reaction time and impaired vigilance, attention, body balance and coordination of extraocular muscles. The subjects assessed themselves mentally slow, muzzy and impaired by performance on visual analogue scales still 3 hr after injection. Critical flicker discrimination was impaired and some respiratory depression still present at 4.5 hr after administration. Oxycodone elevated plasma prolactin at 1.5 and 3 hr while growth hormone levels remained unaffected. We conclude that the profile of psychomotor decrement produced by this mu-opioid agonist closely resembles that of agonist-antagonist analgesics.