The major cystic fibrosis (CF) mutation, ΔF508, is associated with one haplotype (B) determined by the two polymorphic markers, XV2C and KM19. This haplotype is rare (15%) among non-ΔF chromosomes. Its frequency among non-ΔF508 CF chromosomes is 50% with variation between populations. One hypothesis for the high frequency of CF haplotype B chromosomes suggests that there was a selective advantage for CF mutations on this specific "background" as a result of epistatic selection at other closely linked loci. Since the XV2C and KM19 markers are located 200kb 5′ to the CF gene and span only 60 kb, an extended haplotype analysis was needed to test this hypothesis. Haplotypes were determined for 183 CF and 120 non-CF Israeli chromosomes at the XV2C and KM19 loci and at three intragenic polymorphic sites (GATT in intron 6A, TUB18 in intron 19, and 24M in exon 24). Among the studied chromosomes the frequency of non-ΔF508 CF chromosomes associated with haplotype B was 70% (88% among Ashkenazi CF chromosomes). Nine mutations (ΔF508, W1282X, G542X, N1303K, 3849+10 kb C→T, Q359K/T360K, S549I, S549R, and 1717-1G→A) were identified among the studied chromosomes. These mutations accounted for 96% of CF chromosomes of Ashkenazi origin. Haplotype B was associated with seven of these (ΔF508, W1282X, G542X, N1303K, Q359K/ T360K, S549R, and 1717-1G→A). The extended haplotype analysis revealed that in five of the seven mutations associated with the haplotype B, 97% of the chromosomes shared the same intragenic haplotype, 212. The variation found in 3% of the chromosomes was only in the GATT repeat. Two mutations, W1282X and 1717-1G→A, were associated with a completely different intragenic haplotype, 121. The results of this study indicate that grouping of CF chromosome by haplotype analysis spanning a small extragenic region might not be sufficient. In addition, the results of the extended haplotype analysis indicate that all the studied CF chromosomes that carry the same mutation derived from the same origin. Furthermore, the results indicate that the majority of the CF mutations are associated with the same extended haplotype, supporting the selective advantage hypothesis.