Wilms' tumor (WT) is the most common renal malignancy of children. While most occur sporadically, a small percentage are familial or occur as part of a developmental syndrome. Classic WTs exhibit a triphasic histologic pattern composed of blastema, epithelium, and stroma. Occasionally, heterologous elements may also be observed. In this study we investigated a series of four WTs that occurred within a single familial aggregate and contained focal areas of neural differentiation. The tumors were evaluated histologically for the presence of neural elements and immunohistochemically for expression of neural-related markers. Genetic linkage analysis was performed on 3 of the 4 WTs. In addition to the classic triphasic histology, the WTs contained tumor rosettes (4/4), ganglion cells (2/4), foci of ganglioneuromatous differentiation (2/4), and anaplasia (1/4). Staining for chromogranin, S-100, synaptophysin, vimentin, and neuron-specific enolase was positive in all 4 tumors within the areas of neural differentiation whereas staining for CD99 (013) and glial fibrillary acidic protein was negative. Linkage analysis studies suggest that the familial predisposition gene segregating in this family is at 19q13.4. To our knowledge, this is the first reported series of WTs with neural differentiation that occurred within a single family aggregate. Genetic linkage analysis of this family is consistent with linkage to the FWT2 WT predisposition gene at 19q13.4. We propose that these tumors may represent a unique manifestation of tumor susceptibility in this family.