The first cases of orogenital sessile papillomas associated with a novel gammaherpesvirus and papillomavirus were recently reported in freeranging Atlantic bottlenose dolphins (Tursiops truncatus). The tumors appear to be sexually transmitted and are now occurring in epidemic proportions in some coastal areas. This study describes the hematological, biochemical, and immunological findings in free-ranging bottlenose dolphins with orogenital papillomas from the coastal waters of South Carolina and Florida. Blood samples were obtained from 22 dolphins with papillomas and 86 healthy dolphins. Few statistically significant differences were found for hematological and serum chemistry variables. Serum iron was significantly lower and serum bicarbonate significantly higher in dolphins with orogenital papillomas compared with healthy dolphins. However, dolphins with tumors had multiple abnormalities in serum proteins and immunologic parameters. Serum protein electrophoresis results demonstrated significantly elevated levels of total globulin, total alpha globulin, and alpha-2 globulin in dolphins with orogenital papillomas. Gamma globulins were also elevated in dolphins with orogenital papillomas although not significantly. Innate immunity was up-regulated in dolphins with tumors. Granulocytic and monocytic phagocytosis and superoxide respiratory bursts were significantly higher in dolphins with orogenital tumors compared with healthy dolphins.