Background: Antithrombin (AT) is the major inhibitor of coagulation. In people, hypoantithrombinemia is associated with hypercoagulability, thrombosis, and poor prognosis. Veterinary studies, however, have not demonstrated similar prognostic significance. Thus, AT activity (ATA) in dogs currently is interpreted based on human medicine guidelines. Hypothesis: ATA can serve as a prognostic marker in dogs, as has been shown in people. Objectives: (1) To describe the clinical and clinicopathologic findings, diagnoses, and outcome of dogs with decreased versus normal ATA, (2) to identify diseases and mechanisms associated with hypoantithrombinemia, and (3) to assess ATA as a prognostic indicator. Animals and Methods: Retrospective study of 149 dogs with ATA measurement during their disease course. Results: Hypoantithrombinemic dogs had a higher proportion of leukocytosis, hemostatic abnormalities, hypoalbuminemia, and hyperbilirubinemia versus dogs with normal ATA. Hypoantithrombinemia commonly was present in immune-mediated hemolytic anemia (IMHA), pancreatitis, hepatopathy, and neoplasia. It was associated with higher risk of mortality in the entire study population and for specific diseases (eg, IMHA, neoplasia). The odds ratio for mortality significantly and progressively increased when ATA was <60 and <30% (9.9, 14.7, respectively). A receiver operating characteristics analysis of ATA as a predictor of mortality showed an area under the curve of 0.7, and an optimal cutoff point of 60% yielded sensitivity and specificity of 58 and 85%, respectively. Conclusions and Clinical Importance: In dogs, ATA <60% indicates increased mortality risk, similarly to human patients, but ATA has limited value as a single discriminating factor in the outcome.