This study was undertaken to determine whether defects in leukocyte function or in genes at the MHC play a role in the etiology of either localized (LJP) or generalized (GJP) juvenile periodontitis. Thirteen LJP and five GJP patients (ranging in age from 13 to 22 years) and their matched controls were compared with respect to selected leukocyte functions and HLA phenotypic frequencies. The results of these studies indicated that there were significant decreases in the phagocytic and chemotactic abilities of polymorphonuclear leukocytes (PMN) in both LJP and GJP. All JP patients displayed intrinsic cell defects in chemotaxis compared with controls; in addition, some patients displayed multiple defects, including those which were serum-associated. Also, there appeared to be a significant association between JP and HLA-DR2 and HLA-A33 phenotypes. Fifty percent of the JP patients were HLA-DR2-positive, whereas only six percent of the matched controls were positive. Thirty-six percent of JP patients were HLA-A33-positive, whereas none of the controls was positive. The association seen with DR2 may be due to sampling, since there were no significant differences between the JP cases and a larger unmatched control sample which was not evaluated for periodontal disease. We conclude from these data that increased susceptibility of some patients to a very aggressive and destructive form of periodontal disease (JP) is based on defects in PMN responsiveness. Further investigations are necessary to determine whether these defects are under genetic control.