We have previously shown that B16-A (H-2b) murine melanoma cells, when cultured in vitro for more than ten passages, have an undetectable or reduced expression of H-2Kb and Db antigens, respectively. We have now studied the possibility to restore H-2 expression (measured by quantitative antisera absorption) in B16-A cells either by a limited (30 days) period of in vivo growth or by treatment with immune interferon. In vivo transplants in allogeneic H-2k or H-2d mice and in H-2-compatible but Mls and multiple non-H-2 loci incompatible mice restored the normal expression of Kb and Db antigens. Cells obtained from tumors grown in syngeneic or in minor histocompatibility antigens-allogeneic mice showed only a weak increase in Db antigens. Such induction of H-2 expression appears to be mediated by the host's immune system, since (1) cells obtained from tumors grown in allogeneic BALB/c nude mice expressed much lower levels of H-2 antigens than those from tumors grown in normal BALB/c mice, and (2) it was possible to induce H-2 expression by growing B16 cells in syngeneic C57Bl/6 mice previously allostimulated with unrelated BALB/c tumor. In vitro treatment with immune interferon restored the expression of both Kb and Db antigens. We hypothesize that H-2 reexpression on B16 cells grown in allogeneic hosts could take place via the nonspecific components of the immune response, such as immune interferon.