OBJECTIVE To compare clinical signs, laboratory test results, and imaging findings between dogs with suspected anaphylaxis and dogs with sepsis. DESIGN Retrospective case-case study. ANIMALS 10 dogs with suspected anaphylaxis and 22 dogs with confirmed sepsis that met the criteria for systemic inflammatory response syndrome. PROCEDURES Medical records for dogs in each group were reviewed and data extracted regarding signalment; reason for hospital admission; physical examination findings; results of CBC, serum biochemical analysis, coagulation testing, cytologic examination, and microbial culture; and imaging reports. RESULTS All dogs in the anaphylaxis group fulfilled the criteria for systemic inflammatory response syndrome. Dogs in both groups had gastrointestinal signs, lethargy, mentation change, and bleeding abnormalities. Dogs with suspected anaphylaxis had a significantly higher eosinophil count and serum alanine aminotransferase activity and lower blood pH than dogs with sepsis. Dogs with sepsis had a significantly higher band neutrophil count, serum globulins concentration, and serum alkaline phosphatase activity and lower serum glucose concentration. Dogs in both groups had intracavitary free fluid and ultrasonographic findings of thickened intestines, gas or fluid-filled intestines, and a thickened gallbladder wall. CONCLUSIONS AND CLINICAL RELEVANCE Clinical signs, laboratory values, and imaging findings may be similar in dogs with sepsis or anaphylaxis. Given the marked difference in prognosis and treatment, early differentiation is important. Anaphylaxis should be considered if a septic nidus cannot be identified, and supportive care should be considered for such patients.