Based on the finding that 3-acetoxy-2-pyridone had reproducible activity against murine P-388 lymphocytic leukemia, derivatives in this series were synthesized and evaluated to determine structural parameters important for activity. Of the 32 compounds tested, 10 were active. At least two oxygen-containing functional groups are required for P-388 activity, and the 2,3-isomeric arrangement provides the greatest activity. Carbamate or acyloxy groups in the 3-position produced the most active 2-pyridones.