The effect of phenytoin therapy on periodontal indices, plaque microbiology, and gingival overgrowth was studied. Plaque, gingivitis, and calculus indices and pocket depth were recorded for anterior and posterior teeth of 89 subjects partitioned into 5 groups, a control group, and 4 groups of patients receiving phenytoin therapy with differing severity of gingival overgrowth. A survey of the major oral microorganisms present in marginal plaque was also done. The clinical indices increased with increasing severity of overgrowth. Patients with no or minimal overgrowth had clinical indices equal to or less than those of controls. The proportions of the major oral genera in marginal plaque samples from the groups were similar except for the patients with the most severe gingival overgrowth (mentally retarded and institutionalized). The microbe proportions from neither anterior nor posterior sites had a distinct relationship to severity of gingival overgrowth. Furthermore, no differences were found between clinical parameters or plaque microbiology at the anterior sites of patients who had greater anterior than posterior overgrowth. More frequent Correlations occurred among clinical parameters than among microbial percentages or between microbial percentages and clinical indices. This study does not support a specific marginal plaque etiology for phenytoin associated gingival overgrowth.