Objective: This study was conducted to compare plasma levels of methylphenidate over time with single doses of a multilayer-release (MLR) bead formulation and an osmotic, controlled-release oral delivery system (OROS) of methylphenidate in young adults. Methods: This was a randomized, 2-way crossover study in which healthy, nonsmoking young adults (age 18-25 years) were randomized to receive methylphenidate MLR 20 mg QD or OROS methylphenidate 18 mg QD, with a 7-day washout between treatments. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours after dosing. Analysis of plasma samples was conducted by high-performance liquid chromatography with tandem mass-spectrometry detection. Adverse events were monitored by spontaneous reports, laboratory and biochemistry tests, urinalysis, and physical examinations conducted at screening and at the end of the study. Results: Of the 24 subjects originally enrolled, 3 discontinued for personal reasons after the first phase and were not included in the pharmacokinetic analysis. The per-protocol population (11 females, 10 males) had a mean (SD) age of 22 (2) years (range, 19-25 years) and a mean body mass index of 23.6 (3.0) kg/m 2 (range, 19.0-28.5 kg/m 2). The relative AUC0t and Cmax ratios for the MLR methylphenidate formulation compared with the OROS methylphenidate formulation were 110.88% and 121.84%, respectively. When OROS methylphendate values were dose normalized to 20 mg, the relative AUC0-t and Cmax ratios were 100.72% and 111.82%. The mean Tmax for the 2 formulations was 3.71 (2.03) and 4.96 (2.56) hours. Values were significantly higher with the MLR methylphenidate formulation compared with the OROS methylphenidate formulation for AUC 0-4 ( P < 0.001), AUC 0-8 (P < 0.001), AUC 0-12 ( P < 0.001), and AUC 4-12 ( P = 0.037); the AUC 8-12 was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for C max0-4 ( P < 0.001) and C max4-12 (P = 0.002). Thirty-seven adverse events occurred in 11 and 10 subjects during receipt of MLR and OROS methylphenidate, respectively. The most commonly reported adverse events in the intent-to-treat population were catheter-site pain, reported by 8 of 24 subjects (33.3%), and headache, reported by 5 of 24 subjects (20.8%). Conclusions: In these healthy young subjects, MLR methylphenidate was associated with a concentration-time profile that resulted in a higher proportion of the administered methylphenidate dose being delivered in the first 4 hours after dosing compared with OROS methylphenidate while maintaining comparable levels of drug in the latter portion of the dosing interval. This led to maintenance of higher mean levels of methylphenidate throughout the day compared with the closest marketed dose of OROS methylphenidate. The 2 formulations are marketed in dissimilar strengths; however, after correction for administered dose, they yielded similar AUC values.