Objective: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) combined with serum alpha-fetoprotein (AFP) and glypican 3 (GPC3) for early liver cirrhosis and nodular small liver cancer. Methods:The clinical data of 78 patients with early detection of liver cirrhosis and small nodular lesions were retrospectively analyzed. According to the pathological results, they were divided into small liver cancer group (46 cases) and benign lesion group (32 cases). All patients underwent contrast-enhanced ultrasound, serum AFP, and GPC3 levels before operation. The differences in parameters between the two groups were compared, and the value of the three alone or in combination in the diagnosis of small liver cancer was analyzed.Results: The contrast-enhanced ultrasound characteristics of the small liver cancer group were significantly different from those of the benign lesion group (P<0.05). Most of the small liver cancer group showed "fast in and out" performance, while the benign lesion group showed "slow in and slow out" performance. The levels of serum AFP and GPC3 in the small liver cancer group were significantly higher than those in the benign lesion group (P<0.05). Contrast-enhanced ultrasound combined with serum AFP and GPC3 levels in the diagnosis of HCC had the highest accuracy, sensitivity, specificity, positive predictive value, and negative predictive value (P<0.05). Conclusion: Contrast-enhanced ultrasound combined with serum AFP and GPC3 can help improve the differential diagnosis value of small nodular liver cancer in early cirrhosis, and has certain guiding significance for the selection of clinical treatment options.