The protein kinase C activators phorbol 12-myristate 13-acetate (PMA) and mezerein induce differentiation of human monocytic leukemia (THP-1) cells along the monocyte/macrophage pathway of development. The differentiated cells express many important macrophage functions including phagocytosis and the secretion of immunomodulatory cytokines. Mezerein-differentiated THP-1 cells secrete interleukin-1 beta as well as a tumor cell growth inhibitory factor whose basal level is increased in response to interferon-gamma. However, tumoricidal, as opposed to tumoristatic, activity of differentiated THP-1 has not been documented. We report herein that PMA-differentiated THP-1 cells (PD/THP-1) contain elevated levels of MHC class I and class II mRNAs even in the absence of activating factors, and kill HT-29 human colon carcinoma cells when stimulated with recombinant human interferon-gamma. These two characteristics are important components of the macrophage phenotype. The results presented in this study extend previous observations on THP-1 cells by demonstrating that PD/THP-1 cells display a critical, immunologically relevant macrophage function, and therefore, enhance the utility of THP-1 as a model for the in vitro study of immunomodulatory drugs and macrophage-mediated cytocidal processes.