This study was undertaken in an attempt to evaluate the structure-activity relationship of pyrimidinones. Of 20 pyrimidinones tested, only those with a monohalogen substitution at the ortho- or meta-position of the phenyl moiety of the 2-amino-5-halo-6-phenyl-4(3H)-pyrimidinone and ABPP showed statistically significant synergism with cyclophosphamide (CY) against P388 leukemia. Therefore, ABMFPP, AIMFPP, and ABPP were selected for detailed therapeutic evaluation. The pyrimidinone alone had small but significant activity against B16 melanoma with slightly more than a 25% increase in life-span (ILS); however, when used in combination with CY, ABPP or ABMFPP did not yield an effect greater than treatment with CY alone. Only AIMFPP appeared to produce a more or less additive effect with CY. Although none of these pyrimidinones alone had any significant activity against M5076 tumor, the combination with CY (100 mg/kg) produced a range of 102 to 123% ILS and six to nine of 10 mice per group survived >45 days, whereas the treatment with CY alone yielded only a 48% ILS and none survived >45 days. The synergism of the combination therapy was statistically significant (p < 0.01). The combination used against L1210 leukemia also appeared to be superior to the treatment with CY alone and produced 25 to 50% long-term survivors (>30 days). The significance of these findings is discussed in terms of its clinical implications.