Procainamide produces a high incidence of autoimmune reactions in humans. To establish an animal model, we treated three groups of beagle dogs with increasing doses of procainamide HCl (100 to 200 mg/kg) for 11 to 14 months. Sera were examined before and during treatment for antinuclear antibodies (ANA) at a 1:10 dilution by an indirect immunofluorescence assay. The first group of six dogs, which were 1 year old and born in our colony, remained generally negative for ANA. In the second group of four dogs, which were of the same origin but were 3 to 6 years old, two developed ANA after 4 months of treatment. The third group of four dogs were 3 to 6 years old and had been born in the FDA colony to parents originating from another source. These dogs developed ANA after 1 to 2 months and remained generally positive throughout the 11 months of treatment. Dogs of the control groups remained negative except for one that was ANA-positive on several occasions. Three of the ANA-positive treated dogs and the ANA-positive control dog had circulating immune complexes. Serum procainamide concentrations were comparable in dogs of each group; acetylprocainamide was not detected. No alterations were found in serum proteins or in the hemograms, and no clinical signs were seen. The data suggest that age plays a contributory role in the development of this autoimmune response in the dog.