Background: Many adolescents have poor plaque control and sub-optimal toothbrushing behavior. Therefore, we compared the efficacy of an interactive power toothbrush (IPT) to a manual toothbrush (MT) for reducing dental plaque and improving toothbrushing compliance. Methods: In this randomized, parallel single-blind clinical study, adolescents brushed twice daily with either a MT (Oral-B® Indicator soft manual toothbrush) or an IPT (Oral-B® ProfessionalCare 6000 with Bluetooth). Subjects brushed for 2 min, plus an additional 10 s for each 'Focus Care Area'. At screening and Week 2, afternoon pre-brushing plaque was assessed via the Turesky Modification of the Quigley-Hein Plaque Index (TMQHPI), and supervised brushing duration was measured. Results: Sixty subjects were randomized; 98% completed. At Week 2, the mean reduction in whole mouth plaque relative to baseline was 34% (p < 0.001) for the IPT versus 1.7% (p = 0.231) for the MT. For Focus Care Areas, the IPT yielded a 38.1% mean TMQHPI reduction (p < 0.001) versus 6.2% for the MT (p < 0.001). Mean brushing time versus baseline increased 34 s in the IPT group (p < 0.001) while remaining flat in the MT group (p = 1.0). Conclusions: Over 2 weeks, adolescents using an IPT experienced superior plaque reduction and increased overall brushing time versus those using a MT.