The influence(s) of chronic injections of alpha-fetoprotein (AFP), derived from murine amniotic fluid, on the natural history of immunopathology and autoantibody production in New Zealand mice was studied and compared to analagous treatment with albumin, transferrin, or phosphate-buffered saline. Treatment of young New Zealand Black (NZB) mice with AFP, at sera levels of 60-210 micrograms/ml, significantly reduces the titer of IgG1, IgG2, and IgA antierythrocyte antibodies. Similarly, such treated mice have relatively normal levels of splenic Thy-1.2-bearing cells and sera immunoglobulins, at older ages, compared to control groups. In contrast, AFP has no apparent effect on the appearance of either naturally occurring thymocytotoxic antibodies (NTa) or lymphoma. Moreover, the positive features of AFP on disease were only noted for mice treated early in life; AFP had no effect when injected into older animals. Similar, but not as dramatic, changes were observed in NZB x NZW F1 hybrids. It is concluded that in pharmacologic doses, mouse aminotic fluid enriched with AFP may alter the appearance of thymic-dependent autoantibodies.