Greyhounds recover more slowly from certain injectable anesthetics than other dog breeds. previous studies implicate cytochrome P450 (CYP) 2B11 as an important clearance mechanism for these drugs and suggest Greyhounds are deficient in CYP2B11. However, no CYP2B11 gene mutations have been identified that explain this deficiency in Greyhounds. The objectives of this study were to provide additional evidence for CYP2B11 deficiency in Greyhounds, determine the mechanisms underlying this deficiency, and identify CYP2B11 mutations that contribute to this phenotype in Greyhounds. Greyhound livers metabolized CYP2B11 substrates slower, possessed lower CYP2B11 protein abundance, but had similar or higher mRNA expression than other breeds. Gene resequencing identified three CYP2B11 haplotypes, H1 (reference), H2, and H3 that were differentiated by mutations in the gene 3′-untranslated region (3′-UTR). Compared with 63 other dog breeds, Greyhounds had the highest CYP2B11-H3 allele frequency, while CYP2B11-H2 was widely distributed across most breeds. Using 3′-UtR luciferase reporter constructs, CYP2B11-H3 showed markedly lower gene expression (over 70%) compared to CYP2B11-H1 while CYP2B11-H2 expression was intermediate. Truncated mRNA transcripts were observed in CYP2B11-H2 and CYP2B11-H3 but not CYP2B11-H1 transfected cells. Our results implicate CYP2B11 3′-UTR mutations as a cause of decreased CYP2B11 enzyme expression in Greyhounds through reduced translational efficiency. Although the genetic causes underlying racial, ethnic, and population differences in drug disposition and response have been extensively studied in people 1 , relatively little is currently known regarding the source of variable drug effects among different breeds of domestic dog. The only example so far in which the mechanism of a dog breed drug sensitivity has been determined are the Collies and related herding breeds, which were shown to be sensitive to p-glycoprotein substrates because of a 4-base pair deletion mutation in the gene encoding this transporter 2. Another group of dog breeds that have been reported to display significantly different drug response compared with other breed groups are the "Sighthounds". Sighthounds (also known as "Gazehounds") are so-called because they were bred to hunt prey primarily by sight (or gaze), rather than by scent, as is typical of the "Scent hound" grouping of breeds. Modern Greyhounds are a prototypical example of a Sighthound dog breed that have been bred for over 150 years for hunting, coursing, track racing and other purposes 3. It is well known among veterinarians, owners and breeders of Greyhounds (and related Sighthound breeds) that many of these