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Background: An increased frequency of (cystic fibrosis transmembrane conductance regulator) CFTR mutations has been detected in some types of male infertility. The aim of this study was to shed light on the link between CFTR mutations and infertility. Methods: We sequenced the CFTR gene in 294 subjects (190 males) affected by infertility of different origin who underwent assisted reproductive technology (ART). As a control group, we studied 1000 (353 males) unrelated, unselected subjects from the general population of southern Italy. Results: The frequency of CFTR mutations, some of which are detected only by gene sequencing, and of the IVS8 poly(TG)12-poly(T)5-V470 haplotype was significantly higher in obstructive [congenital bilateral absence of vasa defer-entes (CBAVD, five cases)] and secretory (23 cases) azoospermic patients than in the general population. Some patients, primarily those with CBAVD, were compound heterozygous for two mutations. Interestingly, the frequency of the TG12-T5-V470 variant haplotype was significantly higher in severe oligospermic patients (88 cases) and in patients with tubal sterility (74 cases) compared with the general population. Finally, neither the frequency of CFTR mutations nor the frequency of the TG12-T5 variants differed between patients with mild oligospermia (74 cases) and patients with ovulatory sterility (30 cases) compared with the general population. Conclusions: All subjects affected by obstructive or secretory azoospermia should undergo molecular analysis and counselling for CF using gene scanning which has a high detection rate and also reveals rare CFTR mutations. Molecular analysis seems to be less mandatory in other types of male/female infertility. Furthermore, we found that the CFTR TG12-T5-V470 variant haplotype was associated with both severe oligospermia and tubal infertility, thereby implicating the CFTR protein in both spermatogenesis and tubal functionality.