Damselfish neurofibromatosis [DNF], a neoplastic disease characterized by multiple, neurofibromas and malignant schwannomas, is currently the only naturally occurring animal model of human neurofibromatosis type-1. Previous studies of immune function in DNF affected fish indicated the potential for significant immunosuppression in advanced stages of the disease. The current study compares healthy animals with fish captured in the wild bearing spontaneous tumors and with animals bearing experimental tumors transmitted in the laboratory. In order to determine the effects of tumor burden on the immune capabilities of these animals, proliferative responses to mitogens and toward allogeneic cells were tested. The data presented here indicate that animals bearing advanced tumors of experimental origin are profoundly immunocompromised. Similarly, some spontaneous tumor-bearing animals are deficient in proliferative immune responses, and splenocytes from most animals fail to respond to mitogens. However, a proportion of animals with stage 5 spontaneous tumors retain immune reactivity, and are capable of alloreactions comparable to those of normal individuals when stimulated with cells from healthy [4/10, 40%] or other tumor-bearing [4/8, 50%] animals. The contributions of tumor size, distribution and cytokine production to the differential immune impairment are discussed.