Objective: To investigate the alteration of serum microRNAlet-7a (let-7a) level in patients with hepatocellular carcinoma (HCC) and its diagnostic value for HCC. Methods: The let-7a expressions in 60 HCC patients and 46 healthy subjects undergoing health maintenance examination were measured by qRT-PCR. And then the relations of serum let-7a level with clinicopathologic factors of HCC patients were analyzed and the diagnostic efficacy of let-7a for HCC was determined by using a receiver operating characteristic curve (ROC). Results: The relative expression level of serum let-7a in HCC patients was significantly lower than that in healthy population (0.538 vs. 1.571, P<0.05). The serum let-7a level was significantly associated with the formation of tumor emboli (P<0.05), but was irrelevant to all other studied factors that included sex, age, HBV infection, cirrhosis, tumor diameter, tumor number, lymph node metastasis, TNM stage, pathological grade and AFP level (all P>0.05). At an optimal cut-off value of 0.529 of let-7a for diagnosis of HCC, the sensitivity was 79%, the specificity was 71% and the area under the curve (AUC) was 0.77 (95% CI=0.624–0.839) respectively; in combined detection of serum let-7a and AFP for diagnosis of HCC, the sensitivity was 83%, the specificity was 97% and the AUC was 0.92 (95% CI=0.866–0.987), respectively. Conclusion: The serum let-7a level is decreased in HCC patients, which may be potentially used as a new molecular marker for diagnosis of HCC, and its diagnostic efficacy for HCC can be enhanced by combination detection of AFP.