We created a 151-mutation and variant screening panel for cystic fibrosis transmembrane regulator (CFTR) using the Illumina Inc. BeadXpress platform (San Diego, CA). The laboratory developed test was validated using a third-party blinding of a set of 450 samples split with an authority laboratory that provides a large panel CFTR screening and 50 diverse controls admixed randomly. The validation proved the test to be 100% sensitive for the mutations tested and >99% specific. A total of 391 mutations in 11,186 samples tested were confirmed by repeat analysis and sequencing, resulting in an overall confirmed positive rate of 3.5%. Of the mutations detected, 348 were part of the American College of Obstetrics and Gynecology (ACOG) panel (89%) and 43 were non-ACOG (11%). A total of 16 of the 23 ACOG panel mutations were discovered in this cohort, along with 21 different non-ACOG mutation genotypes. We confirmed 6 total patients carrying mutations that would not have been identified by any other commercial panel. The role of a large genotyping panel in carrier screening is discussed relative to the ACOG panel and also in relation to comparative efficacy with targeted massive parallel sequencing.