Severe systemic lupus erythematosus often requires the use of cyclophosphamide in women of reproductive age. As cyclophosphamide is generally avoided during pregnancy because of its teratogenic risk, its impact on fetal survival is poorly understood. This is a case series of lupus patients exposed to cyclophosphamide during pregnancy. We reviewed pregnancies in patients with lupus seen at a large university hospital between October 1986 and September 2003. The pregnancies were evaluated prospectively for cyclophosphamide exposure, lupus activity, and fetal outcome. Comparison was made between pregnancies with severe lupus requiring cyclophosphamide and those that did not. We identified four pregnancies with cyclophosphamide exposure. Two pregnancies were inadvertently exposed to cyclophosphamide early in the first trimester; both resulted in first trimester miscarriages. Two patients were administered cyclophosphamide for severe lupus nephritis and thrombocytopenia during the second trimester. Soon after the administration of cyclophosphamide, both pregnancies ended with fetal demise. Pregnancies exposed to cyclophosphamide for severe lupus flare resulted in a higher rate of fetal losses than pregnancies with severe lupus but not requiring the drug (100% versus 31.25%). In conclusion we present four pregnancies exposed to cyclphosphamide, each ending with pregnancy loss. Based on our experience, the survival of the fetus is strongly in doubt when cyclophosphamide is required to treat lupus in the mother.