Sources of individual variation in plasma methylphenidate (MP) concentrations during usual clinical use are not established. This was evaluated in a series of patients receiving clinical treatment with MP. A single plasma MP concentration was determined in each of 273 children and adolescents ages 5 to 18 years (mean: 11.1 years) who were clinically good responders to MP for the treatment of attention-deficit hyperactivity disorder. MP was given on a twice-daily schedule (mean dose: 25 mg/day) in 40% of patients and three times daily (mean dose: 39.3 mg/day) in 60%. A nonlinear regression model was applied to estimate overall population values of MP clearance and elimination half-life (t1/2), assuming a one-component model with first-order absorption and elimination, and further assuming that clearance is linearly related to body weight. The model incorporated each patient's dosage size and schedule, body weight, and time of the plasma sample. Iterated solutions of best fit were: t1/2, 4.5 hours (95% confidence interval [CI]: 3.1-8.1 hours), and apparent clearance, 90.7 ml/min/kg (95% CI: 74.6-106.7 ml/min/kg). The model explained 43% of the overall variance in MP concentrations (r2 = 0.43, p < .001). In a small subsample (N = 16), a second plasma sample was drawn at the same time of day and at the same dose; the correlation between the two concentration values was 0.83. The relatively noninvasive approach used in this study allows the assessment of pharmacokinetic properties of medications under conditions of appropriate clinical use in special populations such as children, adolescents, and the elderly.