We studied the distribution pattern of major histocompatibility complex (MHC) products in a large series of normal and pathologic liver specimens by an indirect immunoperoxidase method. Class I MHC (HLA-A, B, C) antigens were present either on sinusoidal lining cells (SLC) only, producing a "sinusoidal pattern" (SP), or in addition on the liver cell membrane, producing a "honeycomb pattern" (HCP). The presence of a SP correlated well with the absence of piecemeal necrosis (PMN) (p less than 0.001). The presence of a diffuse HCP was not disease-specific; however, a focal HCP restricted to the periportal area was found in a significantly larger number of liver specimens demonstrating PMN (p = 0.0056). Class II MHC (HLA-DR) antigens were found on the surface and in the cytoplasm of SLC. In a significantly larger number of liver specimens demonstrating PMN, a more extensive expression of class II MHC antigens was observed in the periportal area and in areas of spotty necrosis (SN) (0.01 less than p less than 0.02). These results suggest that in areas of PMN and SN, HLA-antigens may play an important role, and may create the microenvironment necessary for optimal T-lymphocyte triggering, proliferation and effector function. Alternatively, adverse effects may result from the high level of HLA-DR expression in areas of PMN and SN.