Technical Abstract: Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the U.S., is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Matched pairs of infected cases and uninfected controls were identified among 3,545 sheep and used in a genome-wide association study. One single nucleotide polymorphism (SNP) in the ovine transmembrane protein (TMEM154) exceeded genome-wide significance (adjusted p-value 1.6 x 10**-**4). The ovine TMEM154 coding region contained five missense and three frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection, while a third haplotype with lysine (K) at position 35 was not. The E35 haplotypes were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 130 naturally exposed pairs of ewes. The odds of infection for ewes with one copy of a TMEM154 E35 allele were 69 times greater than the odds for those without (p-value <0.0001, 95% CI 12-2,800). In a combined analysis of cohorts from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.71 times greater for sheep with a full-length TMEM154 E35 allele (p-value <0.0001, 95% CI 2.33-3.14). Although rare, some sheep carried homozygous TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection, and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.