Abstract: Comparative reproductive activities of chloroquine, mefloquine and sulphadoxine-pyrimethamine were explored in albino Wistar rats and semen from West African Dwarf Buck (WADB) with a view to elucidating the mechanism of action of these drugs on malereproduction. Five adult male rats were administered 0.5 mL distilled water and served as the control. Five rats each were administered orally chloroquine (10 mg kg -1 b.w.), mefloquine (10 mg kg -1 b.w.) and sulphadoxine-pyrimethamine (5 mg kg -1 b.w.) orally, for four weeks. Each group had it`s own recovery group. Sperm counts, motility and morphology were reduced in rats treated with these drugs in the order mefloquine (p<0.05)> chloroquine > sulphadoxine-pyrimethamine. There was an appreciable recovery in the motility of sperms in all recovery groups. Semen samples from WADB were extended separately with chloroquine, mefloquine and sulphadoxine-pyrimethamine. Extender 1 (first control) had no PENSTRIP (Penicillin and Streptomycin combination) while extender 2 (standard extender; second control) had PENSTRIP. Semen in extenders 3, 4 and 5 were treated with chloroquine, mefloquine and sulphadoxine-pyrimethamine, respectively. Spermatozoa progressive motility in these extenders examined under the microscope at 24 h for 5 days significantly reduced in mefloquine (p<0.01), slightly with chloroquine and unchanged with sulphadoxine-pyrimethamine. The pH of the extenders was significantly reduced in duration dependent manner in mefloquine while it remained unchanged with chloroquine and sulphadoxine-pyrimethamine. The results suggest the safety of sulphadoxine-pyrimethamine and chloroquine in preservation of semen ex vivo while the negative impact of mefloquine could reside within the testis or epididymis.