Background: This study explored the effect of liver resection on perioperative circulating tumor cells (CTCs) and found that the prognostic significance of surgery was associated with changes in CTC counts in patients with hepatocellular carcinoma (HCC). Methods: One hundred thirty-nine patients with HCC were consecutively enrolled. The time-points for collecting blood were one day before operation and three days after operation. CTCs in the peripheral blood were detected by the CellSearch (TM) System. Results: Both CTC detection incidence and mean CTC counts showed greater increases postoperatively (54%, mean 1.54 cells) than preoperatively (43%, mean 1.13 cells). The postoperative CTC counts increased in 41.7% of patients, decreased in 25.2% of patients and did not change in 33.1% of patients. The increase in postoperative CTC counts was significantly associated with the macroscopic tumor thrombus status. Patients with increased postoperative CTC counts (from preoperative CTC < 2 to postoperative CTC >= 2) had significantly shorter disease-free survival (DFS) and overall survival (OS) than did patients with persistent CTC < 2. Patients with persistent CTC levels of >= 2 had the worst prognoses. Conclusions: Surgical liver resection is associated with an increase in CTC counts, and increased postoperative CTC numbers are associated with a worse prognosis in patients with HCC.