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Cystic fibrosis (CF) is a life-threatening and common genetic disorder. Cystic fibrosis newborn screening (CF NBS) has been implemented in many countries over the last 30 years, becoming a widely accepted public health strategy in economically developed countries. False-negative (FN) cases can occur after CF NBS, with the number depending on the method. We evaluated the delayed diagnosis of CF, identifying the patients who had false-negative CF NBS results over 26 years (1992–2018) in Tuscany, Italy. The introduction of DNA analysis to the newborn screening protocol improved the sensitivity of the test and reduced the FNs. Our experience showed that, overall, at least 8.7% of cases of CF received FNs (18 cases) and were diagnosed later, with an average age of 6.6 years (range: 4 months to 22 years). Respiratory symptoms and salt-loss syndrome (metabolic hypochloremic alkalosis) are suggestive symptoms of CF and were commons events in FN patients. In Tuscany, a region with a high CFTR allelic heterogeneity, the salt-loss syndrome was a common event in FNs. Therefore, we provided evidence to support the claim that the FN patients had CFTR mutations rarer compared with the true-positive cases. We underline the importance of vigilance toward clinical manifestations suggestive of CF on the part of the primary care providers and hospital physicians in a region with an efficient newborn screening program.