Objective: Guanfacine extended release (GXR) is a selective α_2A-adrenoceptor agonist that is shown to be an effective nonstimulant treatment for the symptoms of attention-deficit/hyperactivity disorder. This report documents the time course and predictors of symptom efficacy and sedation-related adverse events (AEs) that emerge during GXR treatment throughout 3 randomized, placebo-controlled, double-blind trials of the drug. Method: Analysis of data from 3 GXR clinical trials. Results: Few variables related to the study participants or their treatment regimen affects the emergence or magnitude of sedation-related AEs. The best predictor of sedation is treatment duration, with the likelihood of sedation-related AEs decreasing with increasing time on medication. Sedation-related AEs are not predicted by the actual dose a participant receives, the magnitude of any dose changes, or the relationship between dose received and the magnitude of dose changes. Rates of discontinuation because of sedation-related side effects average 6.3% for GXR-treated participants and 0.5% for placebo-treated participants across the three trials. Conclusion: These results suggest that acclimation to GXR may minimize the risk for, and magnitude of, sedation-related AEs. (J. of Att. Dis. 2010; 13(5) 532-538)