We examined the incidence of other malignancies in 924 Waldenström's Macroglobulinemia (WM) patients and their kin. A total of 225 (24.3%) patients had ≥1 additional malignancy, with 63% predating the WM diagnosis. The most common gender-adjusted malignancies were prostate (9.4%), breast (8.0%), non-melanoma skin (7.1%), hematologic (2.8%), melanoma (2.2%), lung (1.4%) and thyroid 1.1%). Among hematologic malignancies, all 13 cases of diffuse large B-cell lymphoma and 4 cases of acute myelogenous leukemia were diagnosed after WM, and were therapy-related. Familial WM subgroup analysis showed a higher incidence of prostate cancer (P=.046) in sporadic WM patients, while patients with familial WM had a higher incidence of lung cancer (P=.0043). An increased incidence of myeloid leukemias (P<.0001) was reported among kin of familial WM patients. These data reveal specific cancer associations with WM, and provide a basis for exploratory studies aimed at delineating a common genetic basis. Additionally, these studies suggest specific cancer clustering based on familial predisposition to WM.