Melanotic schwannomas (MSs), variably associated with the Carney complex, are rare tumors that usually involve spinal nerve roots but may occur in other locations. Clinicopathologic evaluation poorly predicts the behavior of MS. Fewer than 200 cases have been reported. We report a series of 40 well-characterized MSs, one of the largest series to date. The tumors were comprehensively evaluated, and clinical follow-up was obtained. Immunohistochemistry for S100 protein, Melan-A, HMB45, tyrosinase, glial fibrillary acidic protein (GFAP), EMA, SMARCB1, Ki-67 antigen, ASMTL, and the Carney complex-associated PRKAR1A gene product was performed using commercially available antibodies and the Ventana Ultraview detection system. Gene microarray study was conducted on formalin-fixed, paraffin-embedded blocks from 10 MSs and the results compared with previous data from melanoma and schwannoma. Differentially expressed genes were selected at >3-fold and P<0.001. The Fisher exact test was used for statistical analysis. The tumors occurred in 18 male and 22 female patients (mean age 41 y; range, 11 to 84 y) and involved the paravertebral nerve roots (N=31), mediastinum (N=3), sacrum, cauda equina, para-aortic region, fifth cranial nerve, buttock, and cerebellum (N=1 each). Two patients had known Carney complex, and 1 patient also had a cutaneous myxoma, suggestive of Carney complex. The tumors expressed S100 protein (21/25, 84%), Melan-A (23/25, 92%), HMB45 (25/25, 100%), tyrosinase (25/25, 100%), GFAP (0/24, 0%), EMA (0/9, 0%), SMARCB1 (retained in 25/25, 100%), and ASMTL (5/19, 26%); PRKAR1A expression was lost in 7/20 cases (35%). Ki-67-labeling index was <5% in 23/25 cases (92%) and 5% to 10% in 2/25 cases (8%). Gene expression profiling showed significant differences between MS, melanoma, and conventional schwannoma. Clinical follow-up (26/40, 65%; mean 55 mo; range, 1 to 300 mo) showed local recurrences in 9/26 (35%) and metastases in 11/26 (44%) patients. Fourteen patients were alive without disease, 5 were alive with disease, and 7 had died of disease. Only a mitotic rate >2/10 HPF correlated with metastases (P=0.008). The clinicopathologic features of tumors with and without psammoma bodies were identical. We conclude that MSs are distinctive malignant tumors, rather than benign neoplasms with occasionally unpredictable behavior, and propose their reclassification as "malignant melanotic schwannian tumors." Loss of PRKAR1A expression suggests a link to Carney complex, even when this history is absent.