Objective: To assess the accuracy of pulse oximetry screening for critical congenital heart defects (CCHDs) in a setting with home births and early discharge after hospital deliveries, by using an adapted protocol fitting the work patterns of community midwives. Study design: Pre- and postductal oxygen saturations (SpO2) were measured ≥1 hour after birth and on day 2 or 3. Screenings were positive if the SpO2 measurement was <90% or if 2 independent measures of pre- and postductal SpO2 were <95% and/or the pre-/postductal difference was >3%. Positive screenings were referred for pediatric assessment. Primary outcomes were sensitivity, specificity, and false-positive rate of pulse oximetry screening for CCHD. Secondary outcome was detection of noncardiac illnesses. Results: The prenatal detection rate of CCHDs was 73%. After we excluded these cases and symptomatic CCHDs presenting immediately after birth, 23 959 newborns were screened. Pulse oximetry screening sensitivity in the remaining cohort was 50.0% (95% CI 23.7-76.3) and specificity was 99.1% (95% CI 99.0-99.2). Pulse oximetry screening was false positive for CCHDs in 221 infants, of whom 61% (134) had noncardiac illnesses, including infections (31) and respiratory pathology (88). Pulse oximetry screening did not detect left-heart obstructive CCHDs. Including cases with prenatally detected CCHDs increased the sensitivity to 70.2% (95% CI 56.0-81.4). Conclusion: Pulse oximetry screening adapted for perinatal care in home births and early postdelivery hospital discharge assisted the diagnosis of CCHDs before signs of cardiovascular collapse. High prenatal detection led to a moderate sensitivity of pulse oximetry screening. The screening also detected noncardiac illnesses in 0.6% of all infants, including infections and respiratory morbidity, which led to early recognition and referral for treatment.