Prognostic blood biomarkers for patients with uveal melanoma have not been identified. Tumor monosomy-3 is strongly associated with the development of metastatic disease. Tumor expression of human leukocyte antigen class I molecules and insulin-like growth factor (IGF)-1 receptor has also been associated with the development of metastatic disease. The relationship of blood levels of the human leukocyte antigen-class-I-associated β-2 microglobulin (β2M), IGF-1, and its binding protein, IGFBP-3, with tumor monosomy-3 was evaluated. Blood was drawn from patients with a clinical diagnosis of primary uveal melanoma without metastatic disease before fine-needle aspiration biopsy at the time of brachytherapy or enucleation. Tumor chromosome 3 status was determined by fluorescence in-situ hybridization. β2M, IGF-1, and IGFBP-3 levels were determined using enzyme-linked immunosorbent assays. A total of 76 patients were studied; 47 (62%) underwent brachytherapy and 29 (38%) underwent enucleation. Thirty-three (43%) of the tumors manifested monosomy-3. Most tumors were large, located in the choroid, mixed cell type, and nuclear grade 2. Most tumors did not manifest extraocular extension. Blood levels of IGF-1 and IGFBP-3 were not associated with tumor monosomy-3. In contrast, increases in blood β2M (P≤0.02) were associated with tumor monosomy-3. The independent association of increased blood level of β2M and tumor monosomy-3 status was confirmed in multivariable analysis. In conclusion, measurement of blood levels of β2M in patients with primary uveal melanoma may have prognostic value and may help guide surveillance and adjuvant therapy recommendations.