Misalignment of the jaw in sheep, which has long been considered a genetic condition, occurs in most sheep breeds, and culling of affected animals is recommended. Severe mandibular inferior, where the mandible is shorter than the maxillary, can lead to premature death due to starvation. A German breeding trial of affected sheep produced greater than 60% affected lambs and they estimated jaw misalignments were due to dominant and recessive gene effects. A genome wide association study was conducted using the OvineSNP50 marker set to genotype ewes that either produced unaffected lambs (n = 712) or at least 1 affected (n = 252) lamb during their lifetime. Large numbers of animals from multiple breeds improves the odds for detecting true positively associated genomic regions in multiple genetic backgrounds. Jaw misalignment was categorized as severe, greater than 1.3 cm longer maxillary, moderate, between 0.3 and 1.3 cm longer maxillary, mild, between 0.05 and 0.29 cm longer maxillary, and normal, no misalignment within 24 h of birth. Ewes were Rambouillet, Polypay, and Columbia breeds which produced a total of 8321 purebred and crossbred lambs over 13 y with 3.9% of lambs presented with mandibular inferior. Year of lamb birth was significant (P < 0.01) with lambs born in 2009 having more misaligned jaws compared with all other years. Sex of lamb was significant (P < 0.01) with a greater frequency of misaligned jaws in male lambs. Breed of lamb sire (P > 0.52), ewe age (P > 0.32), and breed of ewe (P > 0.08) did not affect lamb jaw alignment. A recessive model accounting for breed, population cluster, and minor allele frequency identified 2 genomic regions that were significantly (Bonferroni-corrected P < 0.03) and 2 genomic regions that were suggestively (unadjusted P < 2.3 × 10⁻⁶) associated with mandibular inferior. The 2 significant markers were located on chromosome 2, near a gene which affects growth, and chromosome 22 near a gene that plays a role in membrane trafficking. Further evaluation of these genomic regions is required to identify underlying causal mutations, which would be useful in marker-assisted selection for sheep producers.