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Objective: The aim of this study was to determine the effect on family quality of life (QOL) of clonidine (CLON) and methylphenidate (MPH), used alone and in combination, in treating attention-deficit/hyperactivity disorder (ADHD). Methods: Two proxy QOL measures were used in a multicenter, double-blind, placebo-controlled 16-week trial of 122 children, ages 7–12 years, with ADHD. Children were randomized to one of four groups in which they received MPH, CLON, a combination of drugs, or placebo. QOL was measured with the Daily Hassles Scale and the Impact on Family Scale at baseline and at 16 weeks. Results: In a general linear model repeated measures analysis, treatment groups improved over a 16-week period compared to placebo for Daily Hassles and Impact on Family, as well as in symptoms measured by the ADHD Rating Scale. QOL measures correlated moderately with efficacy and symptom measures. Conclusion: This study provides evidence that measures of QOL for the family are sensitive to pharmacological treatment of ADHD. The correlation pattern of the QOL measures with symptom and efficacy variables supported family QOL as a related but separate construct. Clonidine for Attention-Deficit/Hyperactivity Disorder Treatment Study (CAT) Trial Registry Name: Clinicaltrials.gov; ID Number, NCT00031395; URL, http://clinicaltrials.gov/ct/show/NCT00031395?order=8/.