The immune responsiveness of (NZB x NZW) F(1) hybrid mice (NZB/W) has been compared with that of three other strains of mice, A/J, BALB/c, and CBA/J. The antigens used included sheep red blood cells (SRBC), keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA), and human gamma-globulin (HGG). It was found that important strain differences existed in the amount of antibody produced, but the relative immune responsiveness depended very much upon the nature of antigen. By comparison with the other strains tested, NZB/W mice had a higher antibody production to some antigens (SRBC and BSA) but were low responders to others (KLH). Induction of unresponsiveness to HGG by treatment with ultracentrifuged HGG was studied in the strains cited above. NZB/W mice became tolerant after injection of HGG ultracentrifuged at 100,000 g for 2 hr. Similar experiments carried out with another preparation of HGG (centrifuged at 20,000 g for 30 min) failed to reveal any abnormal behavior of NZB/W mice as compared to BALB/c or A/J mice. These results do not support the concept that NZB/W mice possess a general immune hyperreactivity or a relative inability to be made tolerant to protein antigens. However, they do not rule out the possibility that these mice have a genetically determined hyperresponsiveness to some antigens, in particular to nuclear antigens.