Side effect assessment of medicaments on fertility indices may be used as a guide in the development of male contraceptive agents. In this study, 3 analogs of pyrimethamine were synthesized and evaluated for antifertility activity on reproductive indices of male rats. Test compounds were administered in a dosage of 50 mg/kg every other day till 60 days. On the 50th day, the fertility of rats was tested. On the 60th day, the gonadosomatic index and the serum testosterone content were determined. Iso-butyloxy and tertiary-butyloxy caused 40% and 11% reduction in sperm viability, respectively. They also significantly reduced fertility indices. Consequently, iso-butyloxy can be one of the best nominees in this class of compound and a suitable candidate for assessment of mechanism involved in future research activity. To synthesize a more effective agent, increasing the lipophilicity may play a major role in the development of more potent promising male contraceptive agents.