Desmoplastic small round cell tumor (DSRCT) and blastemal-predominant Wilms tumor (WT) share overlapping histologic features, yet accurate distinction is critical because of differing prognosis and treatment. We encountered a neck mass in a young adult with a concomitant abdominal mass. The neck mass was initially concerning for DSRCT on the basis of the poorly differentiated morphology, desmoplastic stroma, and immunoreactivity for desmin and cytokeratin. However, focal triphasic elements and glomeruloid bodies were identified on deeper sections, WT1 immunoreactivity was seen with antibodies to both the amino-terminus and carboxy-terminus, and EWSR1-WT1 rearrangement studies were negative, supporting the ultimate diagnosis of WT. On the basis of the overlapping histologic features of DSRCT and blastemal-predominant WT, we undertook a comparison study of desmin and cytokeratin reactivity patterns. We found that, whereas desmin reactivity was more frequent in DSRCT (11 of 12) than in WT blastema (11 of 22, P=0.024), dot-like perinuclear reactivity was seen with equal frequency in desmin-reactive DSRCT (10 of 11) and WT blastema (10 of 11), illustrating an important diagnostic pitfall. Moreover, we demonstrate coexpression of desmin and cytokeratin in both DSRCT (9 of 12) and WT blastema (11 of 22). Importantly, although dot-like desmin reactivity and coexpression of desmin and cytokeratin are historically associated with DSRCT, we demonstrate that these features can be seen in either DSRCT or blastemal-predominant WT. In these challenging cases, detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.