Medical records from dogs having abdominal ultrasound (US) performed between March 2005 and October 2008 were reviewed for detection of focal liver lesions (FLL) with both cytologic and histologic sampling. Samples were classified as to either the presence or absence of major categories of pathologic processes, including malignant neoplasia, inflammation, hyperplasia/benign neoplasia, vacuolar change, extramedullary hematopoeisis, cholestasis, necrosis, and no microscopic abnormalities. Evaluation of selection bias was performed by review of the relative distribution of cytologic diagnoses for cases with histology compared with cases excluded from the comparison analysis because histology results were not available. Cytology had the highest sensitivity for vacuolar change (57.9%), followed by neoplasia (52.0%). Cytology had the highest positive predictive value (PPV) for neoplasia (86.7%) followed by vacuolar change (51.6%). Cytology had lower sensitivity and PPVs for inflammation, necrosis, and hyperplasia. The ability of cytology to characterize disease in canine FLL varies by pathologic process. Clinicians can have a high degree of confidence when a cytologic diagnosis of neoplasia is given; however, cytology is less reliable for excluding the potential for neoplasia. Cytology has a low sensitivity and PPV for inflammation and a limited diagnostic performance for the diagnosis of vacuolar change.