N-Substituted amides, lactams, and 2-pyridones were examined for their ability to induce leukemic cell differentiation in vitro. These substituted amides were effective inducers of the differentiation of murine erythroleukemia (Friend) cells, as judged by the cellular accumulation of hemoglobin. N-Substitution increases the effectiveness of all classes of agents as inducers of maturation as judged by an increase in potency. N-Cyclohexylacetamide appeared to be a particularly effective compound, causing 92% of the population to synthesize hemoglobin at a concentration which was not inhibitory to cell replication. In the lactam series, an increase in ring size was paralleled by an increase in the potency of unsubstituted compounds, but ring size had less effect on N-substituted lactams. Increasing the chain length of the N-alkyl substituent had little additional effect on a series of lactam and 2-pyridone derivatives; however, some decrease in maximal induction occurred with butyl- and hexyl-substituted 2-pyridones. N-Isopropyl-2-pyridone, selected for further study, was as good an inducer of the HL60 human promyelocytic leukemia as it was of the Friend murine erythroleukemia.