No detectable interferon (IFN) was produced when purified leukocytes from individual blood donors were incubated without induction at 107 cells/ml at 37°C. Mixing the leukocytes from two donors resulted in the production of IFN that was predominantly IFN-γ but contained also some IFN-α/β. The titers varied greatly depending on the combination of the two individuals. The amount of IFN produced did not bear a clear correlation to the HLA A, B, or DQ antigenic differences between the two individuals. A difference in one or two DR alleles was not always a sufficient stimulus for abundant IFN production, but more numerous antigenic DR differences tended to increase the IFN response. © 1990, Mary Ann Liebert, Inc. All rights reserved.