ObjectivesThe study was aimed at assessing the prevalence of syphilis and associated factors among pregnant women with antenatal care follow-up.DesignA health facility-based, cross-sectional study.SettingThe study was conducted in 12 health facilities in Buno Bedele zone, southwest Ethiopia.ParticipantsRandomly selected 920 pregnant women who came to health facilities in the Buno Bedele zone for antenatal care services from May to August 2021 were included in the study. Women with previously diagnosed syphilis and those on treatment were excluded from the study.Outcome measuresBlood samples and data on sociodemographic and other risk factors for syphilis were collected. Sera were screened for syphilis using the one-step rapid syphilis diagnostic test kit, and positive tests were retested using the rapid plasma reagin test. Data were analysed using SPSS V.22. Bivariate and multivariate logistic regression analyses were used to identify risk factors for maternal syphilis at a p value less than 0.05.ResultsThe prevalence of syphilis among pregnant women was found to be 1.4% (95% CI: 0.8% to 2.3%, p=0.002). Women with no formal education (adjusted OR (AOR)=3.6; 95% CI: 1.02 to 13.2, p=0.047), husbands with a history of substance use (AOR=3.3, 95% CI: 1.04 to 10.7, p=0.042), more than one antenatal care visit (AOR=3.5, 95% CI: 1.07 to 10.5, p=0.038), age at marriage under 18 years (AOR=4.3, 95% CI: 2.2 to 7.9, p=0.045) and a woman’s poor knowledge of syphilis (AOR=3.3, 95% CI: 1.04 to 10.4, p=0.042) were significantly associated with syphilis.ConclusionThe prevalence of maternal syphilis in this study area was found to be comparable with the national prevalence. Women’s educational status, husbands’ history of substance use, antenatal care, age at marriage and knowledge about syphilis were the independent predictors of syphilis. Emphasis shall be given to screening all pregnant women, education of women, lifestyle factors and avoiding early marriage.