Male-factor issues contribute to half of all human infertility, and genetic etiologies explain many such cases. Accurate determination of genetic causes of male infertility is important because: a) it explains many cases of previously unexplained male infertility, b) it guides diagnostic and treatment decisions, and c) it has potentially serious implications for genetic risk in offspring, given the capability of reproductive technologies. This study sought to define genetic testing acceptance by patients and the incidence of chromosomal abnormalities, Y-chromosome microdeletions, and cystic fibrosis (CF) mutations in this population. A prospective study of genetic testing uptake and findings in infertile men enrolled in a formal genetic counseling and testing program. Overall, 498 men were evaluated from 1998–2003 in the Program in the Genetics of Infertility (PROGENI) at the University of California, San Francisco. Indications for evaluation included: oligospermia (n = 246), non-obstructive azoospermia (n = 178), congenital absence of the vas deferens (CAVD)/obstructive azoospermia (n = 59), and other (n = 16). Genetic counseling and informed consent were performed non-prescriptively prior to testing. Men with oligospermia and non-obstructive azoospermia were offered chromosome analysis (karyotype) and Y-chromosome microdeletion analysis (multiplex PCR assay and gel electrophoresis). Men with CAVD or obstructive azoospermia were offered CF mutation analysis and poly-T variant analysis. CF mutations were analyzed by common mutation panel, conformation-sensitive gel electrophoresis (CSGE), or DNA sequence analysis. Overall, 202/246 (82%) men with oligospermia, 140/178 (79%) men with nonobstructive azoospermia, and 46/59 (78%) men with CAVD or obstructive azoospermia opted for genetic testing. In oligospermic men, a chromosomal abnormality was detected in 12/126 (10%) and a Y microdeletion observed in 8/202 (4%). In non-obstructive azoospermic men, a chromosomal abnormality was detected in 12/73 (16%) men and a Y microdeletion in 12/140 (9%) men. In men with CAVD or obstructive azoospermia, 21/46 (46%) were found to carry at least one CF mutation (including 3 compound heterozygotes) and 13/39 (33%) had at least one 5T allele (including 1 homozygote). Detection rates of CF mutations varied widely by mutation method and patient ancestry. The incidence of genetic abnormalities in otherwise healthy, infertile men is significant and important. In addition, high rates of patient uptake of genetic testing are observed in a formal, non-prescriptive genetic counseling program.