Depending on the ABO blood group, gonorrhea may affect the titers of isohemagglutinins compared with those of uninfected controls. The isohemagglutinin titers in group O patients were significantly increased (P less than 0.001) against erythrocytes A, B, and AB. In group A patients, only the titer against AB erythrocytes was significantly increased. In group B patients, the titer against AB erythrocytes was significantly lower (P less than 0.001) as compared with that in sera of healthy persons. In six of eight volunteers, an increase in isohemagglutinin titer was observed after an injection of small doses of killed gonococci. However, guinea pigs, rabbit, or small monkeys, i.e., species for which gonococci are not apthogenic, when immunized with gonococci either did not form ABO hemagglutinins or did so with very low titers. In white gonorrhea patients, there was a significantly higher frequency of group B individuals over those with group A, AB, or O. No such correlation was found in black patients. Isohemagglutinins from human sera could be absorbed by cultured gonococci. The implications of these findings in the pathogenesis of gonococcus infection and the problems associated with vaccine development are briefly discussed.