OBJECTIVE: Predicated on a maternal immune response to paternally inherited foreign fetal blood antigens, we hypothesized that maternal-fetal blood incompatibility increases susceptibility to schizophrenia in the offspring. The relation between schizophrenia and maternal-fetal blood incompatibility, arising from the D antigen of the Rhesus (Rh) and the ABO blood group antigens, was examined in a cohort of live-births. METHOD: The data were drawn from the Prenatal Determinants of Schizophrenia Study, a cohort of births occurring between 1959 and 1967 to women enrolled in a Kaiser Permanente Plan-Northern California Region (KP). Adult offspring belonging to the KP from 1981 to 1997 were followed for the incidence of schizophrenia spectrum disorder (SSD). Cox proportional hazards regression was the primary analytic technique. RESULTS: Among second and later born offspring, the adjusted incidence rate ratio (RR(adj)) of SSD was 1.80 (95% CI=0.71-4.58) for the Rh incompatible offspring compared with the Rh compatible offspring; with the males exhibiting higher rate ratio (RR(adj)=2.37; 95% CI=0.82-6.86) than the females (RR(adj)=0.93 95% CI=0.12-7.01). Among all offspring, the RR(adj) for ABO incompatibility was lower and the elevated rate ratio was similarly limited to the males (RR(adj)=1.68; 95% CI=0.76-3.70). For Rh and/or ABO incompatibility, the RR(adj) was 1.57 (95% CI=0.87-2.82). A statistically significant result was detected only for the male offspring (RR(adj)=2.22; 95% CI=1.10-4.47). CONCLUSION: Although the results should be interpreted with caution given the few events of SSD, the findings extend the line of evidence that maternal-fetal blood incompatibility is a risk factor for schizophrenia spectrum disorder; with the strongest evidence to date implicating that the susceptibility pertains only to male offspring.