With the human population of the world currently more than 5.2 billion and growing at an explosive rate, the need for additional forms of readily available contraception appears paramount. To date, contraception techniques in the male have been very limited. The present study demonstrates the ability of pyrimethamine (PYR) to cause spermatogenic arrest and male infertility in mice in a dose-dependent manner. Furthermore, upon cessation of drug administation all animals returned to normal fertility status. It is also suggested that the action of PYR is due to its antifolate action. Thus, PYR represents another approach toward development of a male contraceptive.World human population is now expanding at the rate of 255,000 per day or 93 million per year. At this rate the world population doubles every 39 years. However, the rate is also burgeoning. In 1985 the growth rate was 83 million per year. The current situation of an exploding population will perhaps become even more critical during this coming decade, as there were disproportionately more children born over the past two decades that are now coming ofreproductive age (1). The need for effective contraception is as overwhelming as these statistics. The existing methods of contraception have significant limitations with respect to long-term safety concerns; extensive differences in religious, cultural, and personal attitudes; and awareness of a population problem. These differences require that a wide range of effective and safe contraceptive technologies become readily available. Fortunately, in the western world at least, the notion that contraception is the woman's responsibility is changing. And with this change of attitude, along with recent progress in understanding male reproductive physiology, has begun an intensive search for a reversible male contraceptive agent (2-5).We wish to report that pyrimethamine [PYR; 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine], an inhibitor of dihydrofolate reductase (DHFR; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) used clinically in the control of malaria, produces reversible infertility in two species of laboratory animals. The present study was stimulated by reports that the compound sulfasalazine, which interferes with the absorption of folate (6, 7), caused reduced fertility in male patients (8,9 were sacrificed and examined for gravidity (10). A male mouse was considered fertile if he impregnated any of the females with which he was housed. The number of pregnancies occurring in each test group was also noted. The size and number of embryos in those females that did become pregnant were assessed and the product of these two factors was used as an index of fecundity (11-13).Epididymal Sperm Reserves. At the end of the breeding trials, approximately one-half of the male mice in each group were randomly selected and sacrificed by an overdose of sodium pentobarbital. One epididymis from each of these animals was removed and the epididymal sperm reserves were determined by a technique modif...