OBJECTIVE To identify risk factors for anesthetic-related death in pet dogs and cats. DESIGN Matched case-control study. ANIMALS 237 dogs and 181 cats. PROCEDURES Electronic medical records from 822 hospitals were examined to identify dogs and cats that underwent general anesthesia (including sedation) or sedation alone and had death attributable to the anesthetic episode ≤ 7 days later (case animals; 115 dogs and 89 cats) or survived > 7 days afterward (control animals [matched by species and hospital]; 122 dogs and 92 cats). Information on patient characteristics and data related to the anesthesia session were extracted. Conditional multivariable logistic regression was performed to identify factors associated with anesthetic-related death for each species. RESULTS The anesthetic-related death rate was higher for cats (11/10,000 anesthetic episodes [0.11%]) than for dogs (5/10,000 anesthetic episodes [0.05%]). Increasing age was associated with increased odds of death for both species, as was undergoing nonelective (vs elective) procedures. Odds of death for dogs were significantly greater when preanesthetic physical examination results were not recorded (vs recorded) or when preanesthetic Hct was outside (vs within) the reference range. Odds of death for cats were greater when intra-anesthesia records for oxygen saturation as measured by pulse oximetry were absent. Underweight dogs had almost 15 times the odds of death as nonunderweight dogs; for cats, odds of death increased with increasing body weight (but not with overweight body condition). CONCLUSIONS AND CLINICAL RELEVANCE Several factors were associated with anesthetic-related death in cats and dogs. This information may be useful for development of strategies to reduce anesthetic-related risks when possible and for education of pet owners about anesthetic risks.