Antigens that may be involved in the immune response to uveal melanoma have not been identified. Cellular and humoral responses to melanoma differentiation antigens, as well as to BRCA1-associated protein 1 (BAP1) and α-enolase, alterations of which are associated with metastatic disease, were examined in patients with uveal melanoma. Blood was collected from 66 patients with primary and 13 patients with metastatic uveal melanoma. These included 11 patients treated with immunotherapy. Peripheral blood mononuclear cells were stimulated with gp100, MART-1, tyrosinase, NY-ESO-1, BAP1, and α-enolase peptides and/or proteins, and cytokine production was assessed by bead array or enzyme-linked immunosorbent assay. Autoantibodies to the protein were assessed by enzyme-linked immunosorbent assay. A cellular or humoral response to one or more of the antigens was observed in 23% of the primary and 62% of the metastatic patients tested. Th1 and Th2 cellular and humoral responses to gp100, MART-1, and tyrosinase were observed in primary and metastatic patients. Cellular responses to NY-ESO-1 were not observed nor were Th17-associated responses. Cellular and humoral responses to BAP1 and α-enolase were also observed, predominantly in primary patients with tumor monosomy-3 and in metastatic patients. Individual patients treated with immunotherapy developed new reactivity to MART-1, tyrosinase, and/or α-enolase. Patients with primary and metastatic uveal melanomas manifest spontaneous immune responses to melanoma differentiation antigens, BAP1, and α-enolase. Both Th1-associated and Th2-associated responses are observed and can be modified by therapy. These results may help the development and monitoring of immunotherapy and studies of immune surveillance in uveal melanoma.