Low-grade fibromyxoid sarcoma is a soft tissue sarcoma with recurrent and low metastatic potential, which has characteristic FUS-CREB3L2 or FUS-CREB3L1 fusions. Perineurioma is a peripheral nerve sheath neoplasm, which is usually benign. Low-grade fibromyxoid sarcoma and perineurioma can appear morphologically similar, particularly in small biopsy specimens, and distinction between the 2 entities is important for appropriate treatment. Low-grade fibromyxoid sarcoma is negative for most immunohistochemical markers, whereas perineuriomas stain variably for epithelial membrane antigen, CD34 and claudin-1, a tight-junction associated protein. We studied 15 cases of genetically proven low-grade fibromyxoid sarcoma that at least focally resembled perineurioma, with antibodies to claudin-1 and epithelial membrane antigen. Of these, 11 showed positivity for epithelial membrane antigen and all 15 were positive for claudin-1; in all cases, expression of claudin-1 was equal to or greater than the corresponding epithelial membrane antigen expression. This study emphasizes that claudin-1 is significantly expressed in low-grade fibromyxoid sarcomas. This has implications toward the accurate diagnosis of both tumors, and, as positivity for claudin-1 in low-grade fibromyxoid sarcoma is not previously documented, suggests that there might be underdiagnosis of low-grade fibromyxoid sarcoma. Although positivity for claudin-1 remains useful as an adjunct marker for perineurioma, it should be taken in context with clinical findings, morphology, and the additional immunoprofile.