Background: Males with cystic fibrosis (CF) are infertile. Congenital bilateral absence of the vas deferens (CBAVD) is one of the causes. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have also been found to be an additional cause of male infertility. Therefore, the aims of this study were to investigate the possible involvement of five common CFTR gene mutations (ΔF508, G551D, G542X, W1282X, and R117H) in azoospermia Egyptian infertile males. Materials and Methods: Blood samples were collected from 32 infertile males with Azoospermia In addition, 25 healthy and fertile individuals were included. Fresh semen samples were analyzed by using computer-assisted sperm analysis (CASA). The hormonal profile was investigated using Immulite 2000. Further, screening for CFTR gene mutations were detected by using the Amplification-Refractory Mutation System (ARMS)-PCR technique. Results: Heterozygous CFTR mutations were detected in 4 patients among the studied 32 (12.5%) azoospermic individuals. ΔF508 and R117H are the only 2 detected mutations that gave positive results. Their incidences were 9.4% and 3.1%, respectively. On the hormonal levels, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were increased with no simultaneous effects on the testosterone level; a finding which supports testicular insufficiency rather than the CFTR gene. Conclusion: Whether the latter negatively contributes to azoospermia or not still needs further investigations; on a large-scale male sample. At this time, the importance of CFTR gene mutations study in Egyptians will be more valuable.