The current study was designed to assess the plaque removal efficacy of a novel experimental powered toothbrush (Crest SpinBrush Pro) compared to two leading manual toothbrushes, the Oral-B CrossAction and the Colgate Navigator. In addition, this paper reports the results of two additional studies examining the relative plaque removal efficacy of the two control manual toothbrushes and a number of other manual toothbrushes. The comparative study was a randomized, controlled, examiner-blind, nine-period crossover design, conducted among 127 adult subjects over a two-month period, that examined plaque removal with a new battery-powered toothbrush and two advanced-design manual toothbrushes. During the course of this study, subjects brushed three times with the experimental powered toothbrush and three times with each control manual toothbrush. Study participation was on a voluntary basis following written informed consent of the subjects. Plaque was scored before and after brushing using the Turesky, et al. Modification of the Quigley-Hein Index. Average baseline plaque scores were 2.68 to 2.69 for the three treatment groups. The experimental toothbrush delivered an adjusted (via analysis of covariance) mean difference between baseline and post-brushing plaque scores (i.e., a plaque removal score) of 0.69, while the control toothbrushes delivered adjusted mean differences of 0.46 (Colgate Navigator) and 0.54 (Oral-B CrossAction). All group differences were statistically significant (p < 0.001). The experimental powered toothbrush group had, on average, 49% and 28% greater plaque removal scores than the Colgate Navigator and Oral-B CrossAction groups, respectively. In addition, the Oral-B CrossAction group had, on average, a 16% greater plaque removal score than the Colgate Navigator group. This result was also statistically significant (p < 0.001). Results on buccal and lingual surfaces also demonstrated statistically significantly (p < 0.001) greater plaque removal for the experimental battery-powered toothbrush relative to the control manual toothbrushes.