Some benign tumors categorized as "granular cell tumors" (GCTs) may have heterogenous origins despite their uniform morphologic appearance. Adult GCTs (the usual type), presumed to be of Schwannian origin, are reported to be positive for S100 protein (S100) and neuron-specific enolase (NSE). Congenital GCTs are S100- and NSE-negative and of unknown but probable non-Schwannian origin. To elucidate the histogenesis of adult and congenital GCT, we undertook a comparative immunohistochemical study using paraffin-embedded tissue from 10 cases of GCTs, of which 3 were the congenital type, 6 were the adult type, and 1 was an unusual multiple GCT involving the colonic mucosa. All of the GCTs were negative for keratin, smooth muscle actin, muscle-specific actin, desmin, CD57, CD15, and MAC387. All of the adult and multifocal GCTs involving the colonic mucosa were positive for S100, NSE, alpha-1-antitrypsin (A1AT), CD68, and vimentin. Congenital GCTs, on the other hand, were negative for S100 and NSE but positive for A1AT, CD68, and vimentin. Our study suggests that these two types of GCT have different histogeneses because S100 and NSE are positive in the adult type but negative in the congenital type. They share, however, a common immunophenotype of positive A1AT, CD68, and vimentin. Although this may seem to indicate a common histiocytic origin for adult and congenital GCT, another macrophage marker, MAC387, is negative. Furthermore, CD68 is closely related to the glycoprotein of the lysosomal membrane and is not completely specific for histiocytic cells; for example, it is positive in reactive and neoplastic Schwann cells. Thus, we conclude that positive immunoreactivity for A1AT and CD68 in GCT may be a reflection of the intracytoplasmic accumulation of phagolysosomes and that it does not imply a histiocytic origin for this tumors. We confirm that adult GCT is of Schwannian origin and that congenital GCT is of uncommitted mesenchymal cell origin.