Inhibins are heterodimeric members of the transforming growth factor-β (TGF-β) family, composed of a common α-subunit disulfide-linked to one of two β-subunits (βA in inhibin A, or βB in inhibin B). Gonadal-derived inhibin A and B act in an endocrine manner to suppress the synthesis of follicle stimulating hormone (FSH) by pituitary gonadotrope cells. Roles for inhibins beyond the pituitary, however, have proven difficult to delineate because deletion of the inhibin a -subunit gene results in unconstrained expression of activin A and activin B (homodimers of inhibin b-subunits), which triggers gonadal tumorigenesis and lethal cachectic wasting. Here, we generated mice with a single point mutation (Arg233Ala) in the inhibin a-subunit that prevents cleavage between the pro- and mature domains. In vitro, this mutation blocked inhibin maturation and bioactivity, without perturbing activin production. Characterisation of InhaR233A/R233A mice indicated that FSH levels were elevated 2-3-fold, due to the lack of negative feedback from inhibins, but no pathological increase in activins was observed. While inactivation of inhibin A and B had no discernible effect on male reproduction, female InhaR233A/R233A mice had enlarged ovaries, owing to increased antral follicle and corpora lutea number, and enhanced natural ovulation rates. Fertility analyses revealed that inhibin inactivation resulted in significant embryo-foetal resorptions and severe subfertility, likely owing to disrupted maternal ovarian function. Intriguingly, heterozygous Inha+/R233A mice had enhanced fecundity, carrying twice the number of healthy pups to term during pregnancy, relative to wild-type littermates. These studies have revealed novel roles for inhibins in the establishment and maintenance of pregnancy, and demonstrated that partial inactivation of inhibin A/B is an attractive approach for enhancing female fertility.