Objective:To determine if infants aged 6 to 15 months with frequent parent-reported nighttime awakenings require reduced parental aid during a week of diphenhydramine hydrochloride treatment and 2 and 4 weeks after its discontinuation. Design:Double-blind,randomized,controlled clinical trial. Setting:The study was conducted from May 1,2004,through May 1,2005; patients were recruited nationally. Participants:Forty four participants aged 6 to 15months. Interventions:Placebo or diphenhydraminewas administered in infants 30 minutes before anticipated bedtime. Main Outcome Measures:The primary outcome was dichotomous:a parental report of improvement in the number of night awakenings requiring parental assistance during the intervention week,which ended on day 14.Secondary outcomes were improved sleep during the 2 weeks before days 29 and 43,parental overall happiness with sleep,and improved sleep latency. Results:On June 6,2005,the data safety monitoring board voted unanimously to stop the trial early because of lack of effectiveness of diphenhydramine over placebo. Only 1 of 22 children receiving diphenhydramine showed improvement compared with 3 of 22 receiving placebo.To reach the a priori determined sample size and have a positive outcome (ie,rejecting the null hypothesis),the trial would have needed to enroll 16 more participants in each arm,with 15 of the 16 in the diphenhydramine group and 0 of 16 in the placebo group improving. Conclusion:During 1 week of therapy and at follow-up 2 and 4 weeks later,diphenhydramine was no more effective than placebo in reducing nighttime awakening or improving overall parental happiness with sleep for infants. Objective: To determine if infants aged 6 to 15 months with frequent parent-reported nighttime awakenings require reduced parental aid during a week of diphenhydramine hydrochloride treatment and 2 and 4 weeks after its discontinuation. Design: Double-blind, randomized, controlled clinical trial. Participants: Forty four participants aged 6 to 15 months. Interventions: Placebo or diphenhydramine was administered in infants 30 minutes before anticipated bedtime. Main Outcome Measures : The primary outcome was dichotomous: a parental report of improvement in the number of night awakenings requiring parental assistance during the intervention week, which ended on day 14. Secondary outcomes were improved sleep during the 2 weeks before days 29 and 43, parental overall happiness with sleep, and improved sleep latency. Results: On June 6, 2005, the data safety monitoring board voted unanimously to stop the only 1 of 22 children receiving diphenhydramine showed improvement compared with 3 of 22 receiving placebo.To reach the a priori determined sample size and have a positive outcome (ie, rejecting the null hypothesis) , the trial would have needed to enroll 16 more participants in each arm, with 15 of the 16 in the diphenhydramine group and 0 of 16 in the placebo group improving. Conclusion: During 1 week of therapy and at follow-up 2 and 4 weeks later, diphenhydramine was no more effective than placebo in reducing nighttime awakening or improving overall parental happiness with sleep for infants.