Poly(A) polymerase (polynucleotide adenylyltransferase; ATP:polynucleotide adenylyltransferase, EC 2.7.7.19) was covalently linked to diazobenzyloxymethyl-filters and used to screen the sera from a number of tumor-bearing rats and human cancer patients for antibodies to poly(A) polymerase. Sera from rats that had been inoculated with any of several Morris hepatomas or a mammary adenocarcinoma contained immunoglobulins capable of complexing with poly(A) polymerase. No antibodies to the enzyme could be detected in sera from control animals or from those bearing tumors for short periods of time. Antibodies to poly(A) polymerase were also observed in sera from human patients with leukemia, polycythemia vera, and Wilms tumor. The antibodies were not evident in sera from normal volunteers or from patients with nonneoplastic diseases. These included lupus erythematosus, a disorder in which antibodies are produced against an array of nuclear proteins. Immunoglobulins from the serum of one of the human patients were capable of inhibiting poly(A) polymerase activity in vitro, whereas those prepared from the serum of a normal volunteer did not affect enzyme activity. As determined by the diazobenzyloxymethyl-filter technique, the relative concentration of antibodies in the sera of an individual with leukemia (in remission) increased severalfold during a relapse. These data suggest that the presence of antibodies to poly(A) polymerase may be characteristic of sera from cancer patients and that the relative concentration of these antibodies may be indicative of the disease state.