Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The extent of the contribution of familial/hereditary predisposition to the development of uveal melanoma is largely unknown. Thus we sought to ascertain the frequency of cancers in patients with UM and their family members to identify the prevalence of hereditary/familial predisposition to cancer in these patients. An unselected series of 121 patients with UM seen in a university-based tertiary referral program were consented to the study. Cancer histories (site and age of diagnosis) were obtained for all first- and second-degree relatives. Patients/families were classified as being potentially at high risk for hereditary predisposition if they met any of the following criteria: (1) Diagnosis of UM at age 30 or under, (2) Two or more cases of UM in the family, (3) UM plus at least one other primary cancer in the same patient (excluding non-melanoma skin and cervix cancers due to their strong environmental etiological link). (4) Family history meeting high risk criteria for a known hereditary cancer predisposition syndrome as defined by Hampel et al. (J Med Genet 41(2): 81-91, 2004). One patient had a family history of UM (0.8%). Ten patients (8.3%) had a personal and/or family history consistent with predisposition to a known hereditary cancer syndrome including six with possible hereditary breast, two with hereditary colon and two with hereditary melanomas. Twenty three patients (19%) had a personal history of a second cancer after exclusion of non-melanoma skin and cervical cancers. The frequency of cutaneous melanomas was significantly higher in UM patients than the general population (RR: 2.97, 95% CI: 1.00-6.94). Patients with a family history suggestive of a high risk predisposition to a known cancer syndrome had a significantly higher risk for having a second cancer than the remaining UM patients (P = 0.02). Our results indicate that the frequency of UM patients with high risk for a hereditary cancer predisposition is much higher than earlier estimates (0.6%) and that it could be as high as 11.6%. Our results suggest that cancer phenotypes in these patients are diverse and include cancers other than UM. Thus, alerting ophthalmologists to the need for expanding their cancer family history intake to include other cancers is warranted. It also suggests that patients with a hereditary predisposition to UM have a higher risk for the development of other cancers and that characterization of the germline genetic alterations in these patients is highly warranted.