The pathologic alterations occurring in the gingival tissues of humans immediately following the beginning of plaque accumulation have not heen elucidated previously. Seven males, 22--31 years of age, free of clinical manifestations of dental and periodontal disease, and exhibiting a Plaque Index score of zero for the previous 28 days served as subjects. Plaque control measures were discontinued for 8 days and biopsies were taken from the buccal marginal gingiva of the first premolars on days 0, 2, 4, and 8. Paraffin- and Epon-embedded section, treated with a variety of histochemical stains were analyzed microscopically and cell counts were done on 1-micron Epon section. At 2 and 4 days following the beginning of plaque accumulation, the vessels subjacent to the juctional epithelium exhibited vasculitis and alterations in the perivascular collagen. There was a statistically significant increase in the number of neutrophils residing in the junctional epithelium. By the end of the 8-day period, the number of small mononuclear cells, mostly lymphocytes, in the connective tissues had increased by 3-fold and the area of collagen fiber alteration by 4-fold. In addition, the number of fibroblasts per unit area of connective tissue decreased significantly. Thus, within the period of 8 days following the beginning of plaque accumulation, an early lesion exhibiting many features characteristic of delayed hypersensitivity develops.