Monoclonal antibodies (MAbs) reactive with lymphoid cells are not necessarily specific for lymphoid tissues. Forty MAbs with varying degrees of specificity in lymphoid tissue were tested against a wide battery of nonlymphoid human tissues. Cross-reactivity was identified in 18 of 41 antibodies tested. Based on their reactivities, the MAbs were classified in three groups: (1) antibodies with wide reactivities in normal nonlymphoid tissues, i.e., anti-Leu 4, anti-Leu M1, OKT9, anti-HLA-Dr, anti-Leu M2, Mo-2 (Coulter), anti-Leu 7, BA-1, BA-2, BA-3, J5, and A1G3; (2) antibodies with limited reactivities in nonlymphoid tissues (one or two tissues), i.e., OKT6, anti-Leu 10, Mo-1 (BRL), Mo-2 (BRL); and (3) antibodies without cross reactivities in nonlymphoid tissues, i.e., anti-Leu 1, anti-Leu 2a, anti-Leu 3a, OKT3, OKT10, 3A1, anti-Leu 8, TA-1, Lyt 3, B1, B2, OKMo-1, anti-Leu M3, T200. The reactions can be attributed to the presence of a similar, if not identical, epitope in related or different molecules.