Leu M1 positivity of Reed-Sternberg (RS) cells has been reported. The authors studied the specificity and sensitivity of Leu M1 in Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Within NHL, they particularly selected cases that were confused with HD. The authors also studied S100 antigen to determine the pattern of staining in HD and NHL. Paraffin-embedded sections of 23 HD cases (3 lymphocytes predominate, 10 nodular sclerosing, 10 mixed cellularity) and 22 NHL cases (13 diffuse large cell, 5 diffuse mixed small and large cell, 4 others) were studied using an ABC technic. In 20 of 23 HD cases, RS cells and variants were Leu M1+; most cases contained prominent paranuclear positivity; some had diffuse cytoplasmic staining; and some had apparent staining of the cell surface. Neutrophils were intensely positive for Leu M1 and occasional histiocytes also were labeled. In two of the three negative cases (MC), the neutrophils were only weakly positive, thus suggesting a problem with tissue preparation. Of 22 NHL cases, 15 were totally Leu M1 negative. In six cases, rare or occasional tumor cells contained Leu M1 positivity in either a weak punctate, granular, or surface pattern. In an additional case, extensive pleomorphic cell staining was seen indistinguishable from that observed in RS cells; this case was the fourth recurrence of a primary skin NHL which began two years earlier as a pure small cleaved cell NHL. A total of three cases had positive pleomorphic cells. Some carcinomas were also Leu M1 positive. Concerning S100 antigen, the authors found scattered non-neoplastic cells throughout both HD and NHL samples; no tumor cells stained with this antigen. The negative S100 reaction of RS cells fails to support the argument for a dendritic cell origin. In properly prepared tissue, Leu M1 staining is quite sensitive for RS cells and variants, displaying a characteristic pattern. However, occasional Leu M1 positivity identified in NHL raises doubt as to its complete specificity.