Mice were exposed to fresh cigarette smoke for 1,17, and 38 weeks. After each period the primary and secondary humoral immune response to intraperitoneal inoculation of sheep erythrocytes was studied. Direct and indirect plaque forming cell responses in the spleen and in a pool of cervical and mediastinal lymph nodes, as well as serum hemolytic and hemagglutinating antibodies were examined. Primary plaque forming cell and antibody response to sheep erythrocytes was first enhanced and then depressed by continual cigarette smoke exposure, while the secondary response was unaffected. Serum antibody response to polyvinylpyrrolidone, an immunogen independent of thymus-derived lymphocytes, was not impaired by 41 weeks of cigarette smoke exposure.