BACKGROUND: Syphilis remains a major cause of fetal loss and neonatal mortality in sub-Saharan Africa. Guinea-Bissau is the epicenter of the HIV-2 epidemic, and little is known about the impact of HIV-2 on pregnancy. GOAL: To understand better the impact of maternal syphilis and HIV-2 on the outcomes of pregnancy in Bissau, Guinea-Bissau. STUDY DESIGN: Using a case-control design, maternal syphilis and HIV-2 seropositive results were examined in relation to adverse outcomes of pregnancy. From June 1997 to April 1998, women presenting to the Simao Mendes hospital of Bissau for a delivery or a spontaneous abortion were invited to participate in the study, and 1341 women were enrolled. The 743 control subjects were women who had delivered a term neonate with a birthweight greater than 2500 g that survived the first 28 days of life. The cases were classified into five groups of mothers according to the outcome of pregnancy: stillbirths (n = 185), spontaneous abortions (n = 89), premature deliveries (n = 256), small-for-gestation-age babies (n = 55), and neonatal deaths (n = 13). RESULTS: Among the control subjects, the prevalences of serologic syphilis and HIV infection were 3.9% and 7.9%, respectively. Positive syphilis serology results together with a rapid plasma reagin titer of 1:16 or more were associated with delivery of a stillborn (adjusted odds ratio [AOR], 6.05) and premature delivery (AOR, 2.98). In Bissau, the population-attributable risk fraction of syphilis was 7.2% (95% CI, 2.2-11.9%) for stillbirths and only 2.4% (95% CI, 0-5.8%) for premature deliveries. Spontaneous abortions, delivery of a small-for-gestation-age baby, and neonatal deaths were not associated with positive syphilis serology results. None of these pregnancy outcomes was significantly associated with HIV-2 infection. CONCLUSIONS: The effect of syphilis on the outcome of pregnancy in West Africa is similar to that reported from other parts of Africa. However, because the prevalence of positive syphilis serology results is relatively low, the impact of screening for syphilis on the outcome of pregnancy is likely to be relatively modest. The findings from this study confirm the absence of association between HIV-2 and an adverse pregnancy outcome.