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We evaluated pharmacokinetics and absolute bioavailability of single doses of hydromorphone hydrochloride after administration of 1.0 and 2.0 mg of intranasal (IN) and 2.0 mg of IV hydromorphone hydrochloride. An open-label, randomized, three-way crossover study was conducted in 24 healthy volunteers (13 men and 11 women). IN doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1.0- and 2.0-mg doses, respectively. Blood samples were taken serially from 0 to 16 h after each dose. Plasma hydromorphone concentrations were determined by liquid chromatography-mass spectrometry-mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic varia-bles. Mean hydromorphone bioavailabilities and percent coefficient of variation of 52.4% (22.7) and 57.5% (18.6) were seen after the 1.0- and 2.0-mg IN doses, respectively. Median times to maximum concentration were 20 and 25 min for IN doses. Adverse events included somnolence and dizziness with all routes of administration and a bad taste after IN doses. Dose proportionality for the 1.0- and 2.0-mg IN doses was observed. IN hydromorphone hydrochloride met the minimum requirements for safety and demonstrated rapid nasal drug absorption and clinically relevant bioavailability. Results support further development of this novel hydromorphone hydrochloride nasal spray.