In natural matings, semen delivers spermatozoa and immunoregulatory fluids to the female reproductive tract. Here, a soluble form of CD38 (sCD38) is shown to play an important role in facilitating maternal immune tolerance against the fetus by inducing the development of uterine tolerogenic DCs and forkhead box P3+ (Foxp3+) regulatory T cells. Deficiency of sCD38 in seminal fluid increased the rates of loss of allogeneic fetuses, and this loss was rescued by a direct injection of recombinant sCD38 into the uterus. Thus, seminal sCD38 acts as a pivotal immune suppressor for establishing maternal immune tolerance against the fetus. sCD38 could potentially be used to prevent failed pregnancies.