Hepatocellular carcinoma (HCC) in dogs is relatively uncommon and generally linked to a favorable outcome, although a subset of cases exhibits aggressive behavior. In human oncology, HCC typically presents as a highly malignant neoplasm, and various diagnostic and prognostic indicators—such as the expression of PIVKA-II—are used to assess tumor biology. To explore potential prognostic factors for canine HCC, several histological grading systems were applied, and PIVKA-II immunoreactivity was assessed in 22 surgically treated canine HCCs with a minimum clinical follow-up of two years. Among the studied cases, 19 dogs completed the observation period without recurrence, whereas 3 developed metastatic disease and died. Fifteen of 22 tumors showed positive PIVKA-II staining, but no clear relationship was identified between PIVKA-II expression, prognosis, or histologic grade, although a tendency toward PIVKA-II negativity in low WHO grades and positivity in higher grades was noted. The findings suggest that PIVKA-II cannot be regarded as a malignancy or prognostic marker in canine HCC. Clinical status at presentation remains the main determinant of outcome. To date, histopathological parameters capable of predicting tumor aggressiveness in canine HCC remain undefined. Within this investigation, the WHO histological grading appeared to be the most applicable system.