OBJECTIVE To assess for any association between a history of tibial plateau leveling osteotomy (TPLO) and subsequent development of proximal tibial osteosarcoma in dogs. DESIGN Matched case-control study. ANIMALS 34 client-owned dogs in which proximal tibial osteosarcoma was diagnosed between January 2005 and December 2012 (cases) and 79 dogs without osteosarcoma, matched 3:1 to cases (when possible) by age, breed, and initial examination date (controls). PROCEDURES Information on each case and control was collected from the medical records and other sources regarding date of birth, sex and neuter status, body weight, breed, and whether TPLO had been performed ≥ 1 year ago. A multivariable conditional logistic regression model was constructed to evaluate associations of body weight and history of TPLO with the outcome of proximal tibial osteosarcoma in dogs. RESULTS After adjusting for body weight in the multivariable model, dogs with a history of TPLO were 40 times as likely to develop proximal tibial osteosarcoma as were dogs with no history of TPLO. In addition, each 1-kg (2.2-lb) increase in body weight was associated with an 11% increase in the odds of proximal tibial osteosarcoma. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that dogs with a history of TPLO were at increased risk of developing osteosarcoma of the proximal region of the tibia relative to dogs with no such history. Therefore, it is important for proximal tibial osteosarcoma to be included among the differential diagnoses for new or worsening hind limb lameness in dogs that underwent TPLO ≥ 1 year previously.