BACKGROUND: We demonstrated recently that adeno-associated virus-2 (AAV-2) DNA was detected significantly more frequently in placental trophoblast cells from cases of severe pre-eclampsia than from normal term deliveries. Here, we sought to determine if maternal AAV-2 infection early in pregnancy preceded adverse outcomes resulting from placental dysfunction. METHODS: We collected first trimester maternal serum samples and compared anti-AAV-2 IgM antibody levels (indicating primary infection or reactivation of latent AAV-2) between controls delivered at term (n = 106) and three groups of cases: spontaneous abortions (n = 34), spontaneous preterm deliveries (n = 24) and women with at least one outcome usually attributed to placental dysfunction, including pre-eclampsia, intrauterine growth restriction (IUGR) or stillbirth (n = 20). The seroprevalence of immunoglobulin G (IgG) antibodies against AAV-2 and IgM antibodies against viruses that promote AAV-2 replication [adenovirus and cytomegalovirus (CMV)] were also determined. RESULTS: First trimester maternal IgM seropositivity was 5.6 times more prevalent among pre-eclampsia/IUGR/stillbirth cases (P = 0.0004) and 7.6 times more prevalent among preterm deliveries (P < 0.0001) than among controls. CMV and adenovirus IgM antibodies and chronic AAV-2 infections (IgG seropositivity) were not associated with adverse pregnancy outcomes. CONCLUSIONS: Primary or reactivated AAV-2 infection (maternal IgM seropositivity) early in pregnancy was associated with adverse reproductive outcomes associated with placental dysfunction, including pre-eclampsia, stillbirth and spontaneous preterm delivery.