Premature ovarian failure and reduced fecundity are well-documented consequences of cytotoxic chemotherapy used to treat patients with malignant diseases. To investigate the ability of different hormonal agents to block the effects of cyclophosphamide (CTX) on reproductive function, sexually mature female Long-Evans rats were studied. Model development demonstrated that CTX, 6 mg/kg/day, 5 days/week for 3 weeks, was successful at inducing acyclicity and significantly reducing fertility and fecundity, with acceptable mortality, when compared to higher/lower dosages. Utilizing this model, animals were treated with CTX in combination with an inert vehicle, Lupron, 80 µg/kg every 24 h, Lupron, 40 µg/kg every 12 h, or s.c. progesterone capsules obtaining serum progesterone levels of 20–30 ng/ml. We concluded that progesterone was able to protect the gonad from the negative effects of CTX, maintaining fertility and fecundity rates not significantly different from those of untreated control animals. Lupron given every 12 h had a similar effect on fertility, but failed to protect fecundity (P < 0.001).