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Background: Since January 2015, the Cystic Fibrosis National Newborn Bloodspot Screening (CF-NBS) program has been implemented in Türkiye with two samples of immune reactive trypsinogen (IRT-1/IRT-2) testing. Aims: To evaluate the Turkish national CF screening program, which included patients referred to a tertiary pediatric pulmonology center, to ascertain the optimal cut-off values for IRT-1/IRT-2 and to identify alternative strategies for mitigating the number of late-diagnosed false-negative patients (FNPs) who initially exhibited screen negative results but were diagnosed subsequently based on clinical suspicion. The study also compared NBS-positive patients to FNPs to determine the influence of delayed diagnosis. Study Design: A retrospective cohort study. Methods: Screening for CF was conducted in accordance with the national CF-NBS program within 48-72 hours of birth by collecting a few drops of heel blood on Guthrie paper. A cut-off value of 90 µg/l was accepted for the first IRT, while 70 µg/l was accepted for the second sample. Infants with elevated IRT values in both samples were referred to the CF centers for a sweat test (ST). Based on the diagnosis, the NBS-positive infants referred to our CF center for ST analysis were divided into three groups: CF; cystic fibrosis-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID); and false-positive NBS. In addition, the study included NBS-negative patients who initially received negative screen results but were subsequently diagnosed with CF based on clinical suspicion. Results: Of the 227 NBS-positive infants referred within the study period, 53 (23.34%) were diagnosed with CF (true-positive NBS), 11 were classified as CRMS/CFSPID (4.84%), and 163 were classified as false-positive NBS (71.8%). CF was diagnosed in 66 infants, 53 (80.3%) of whom were confirmed using the NBS test, while the 13 (19.7%) patients who were missed on the NBS test were diagnosed based on clinical suspicion (FNP). The study findings indicate that the IRT/IRT approach exhibited a sensitivity of 80.3% and a positive predictive value (PPV) of 23.3%. Conclusion: The current study is the first to analyze the NBS program for CF using data from the Western Anatolian Region of Türkiye. Due to the low sensitivity and PPV of the IRT/IRT protocol and the high proportion of false-positive infants and FNPs, the current national program is not practicable for Türkiye. False-negative results significantly delay the diagnosis and invalidate the screening objectives. It is essential to establish optimal cut-off values for IRT-1/IRT-2 or revise existing strategies to reduce the number of FNPs missed by the screening program.