The present study was performed to identify risk factors for canine leptospirosis at a tertiary referral institution in northern California from 2001 through 2010 and to describe case characteristics. In this retrospective case-control study, 67 dogs with leptospirosis and 271 controls were evaluated at the William R. Pritchard Veterinary Medical Teaching Hospital (Davis, CA) from March, 2001 , through November, 2010. Medical records of cases and controls were analyzed to identify signalment, exposure history, and clinical signs that increased the risk for a diagnosis of leptospirosis. Among cases, most were vomiting and lethargic and had leukocytosis and azotemia. Total white cell count, neutrophil count, and monocyte count were higher in dogs with leptospirosis, whereas the platelet count was lower. Serum concentrations of urea nitrogen, creatinine, and bilirubin were elevated in dogs with leptospirosis as well. On average, case dogs were hospitalized for 11 days and had hospital bills exceeding $5000. Mortality was 13% of case dogs, with the predominant serovar being Pomona. Dogs with leptospirosis were more likely to reside in the central or south coast (odds ratio [OR]=7.33), Sierra Nevada foothills (OR=4.50), San Francisco Bay area (OR=4.2), and north coast (OR=2.85) of California when compared with controls. Dogs 5-10 years old (OR=3.22) or over 10 years old (OR=2.76) and herding (OR=3.1) or hound breed (OR=4.6) dogs were more likely to have leptospirosis than the control group. Leptospirosis was associated with acute renal failure in older, undervaccinated dogs. The regional distribution, large breed predisposition, and finding of predominantly Pomona serovar suggest wildlife or other contacts as an important route of exposure. Knowledge of risk factors, vaccination history, and clinical signs can increase an index of suspicion for leptospirosis and contribute to improved strategies for prevention of leptospirosis in dogs, understanding of the ecology of the disease for all species, and protection of human health.