Purpose: Despite significant advances in the diagnosis and treatment of sickle cell disease (SCD), most of the >300,000 infants born with SCD will die before the age of 5 years, primarily due to the lack of timely and accurate diagnosis. In high-resource countries, early identification of SCD through newborn screening (NBS) is routine and subsequent delivery of preventive measures and comprehensive care is highly effective in reducing morbidity and early mortality. Despite the proven efficacy of NBS and successful pilot programs across Africa, large-scale implementation remains infeasible in many sub-Saharan countries due to inadequate financial, laboratory, and technical resources. The development and deployment of low-cost, rapid, user-friendly, and accurate diagnostic testing for SCD is imperative. Recently, several promising point-of-care (POC) diagnostics have been developed, but there have been few real-world studies that compare these tests head-to-head, particularly in the setting of NBS, where accurate diagnosis amidst high levels of fetal hemoglobin is critical. Materials and methods: We performed a prospective evaluation of two POC SCD diagnostics (Sickle SCAN and HemoTypeSC) at maternity centers and immunization centers in Luanda, Angola, with confirmation by isoelectric focusing (IEF). To evaluate the real-world feasibility and accuracy, with the guidance of the Angolan Ministry of Health, we planned to test 100 infants ≤6 months of age with each test at 10 different clinical sites (total of 2,000 infants tested). The study was designed to mimic a real-world setting with all POC testing performed and interpreted by local healthcare staff with basic instructions for the use of each test. Results: Of the 2,000 infants tested, 1958 results were included in the final analysis, with the exclusion of 42 tests that were not interpreted in the recommended time frame. Consistent with prior studies in Angola, the burden of sickle cell trait (HbAS, 21.9%) and sickle cell anemia (HbSS, 1.7%) was high. Tests were performed in maternity wards on the day of or following birth (63%) or at immunization centers through 6 months of life (37%). HemoTypeSC took an average of 15 minutes to obtain a result, was repeated 68 times (6.8%) due to invalid results, and was interpreted incorrectly only 4 times (0.4%). Sickle SCAN took an average of 7 minutes to obtain a result, was repeated 2 times (0.2%) due to invalid results, and interpreted incorrectly only 11 times (1.1%). The gold standard of IEF was imperfect with 5.5% of samples needing repeat testing at least once 12 samples with inconclusive results. Importantly, 92% of babies who were diagnosed and informed at the POC followed up in the SCD clinic, compared to the historical 56% who were successfully brought to care during the initial pilot NBS program in Luanda. Conclusion: This study demonstrates the feasibility and accuracy of both HemoTypeSC and Sickle SCAN for diagnosing SCD in newborns in a Luanda, Angola. Given the complexities of testing in the newborn period at busy maternity hospitals, this study suggests that testing at immunization centers using novel POC diagnostics may be a more practical solution to early infant diagnosis programs for SCD. The authors do not declare any conflict of interest