Objective To investigate the serum level of AFP in hepatocellular carcinoma (HCC) patients and the diagnostic value of AFP combined detection of ALT and T-Bil in HCC diagnosis. Methods The serum levels of AFP, ALT and T-Bil in 552 HCC patients and 1857 benign liver diseases patients were detected and compared, and the ratio of AFP/(ALT×T-Bil) was used as the combined diagnostic model of AFP combined with ALT and T-Bil in HCC diagnosis. The receiver operating characteristic (ROC) curves were used to analyze and compare the diagnostic efficacy of AFP and combined diagnostic model in HCC diagnosis. Results The serum level of AFP in HCC patients was significantly higher than that of benign liver diseases patients (P＜0.001), while the serum levels of ALT and T-Bil were significantly lower than those of benign liver diseases patients (P＜0.001). There were significant positive correlations between serum level of AFP and the value of combined diagnostic model with tumor size (r=0.325, P＜0.001; r=0.217, P＜0.001). The area under the ROC curves (AUROCs) of combined diagnostic model in HCC and early HCC diagnosis were 0.869 (95% CI:0.852-0.886) and 0.841 (95% CI:0.812-0.870) respectively, which were significantly higher than those of AFP ［0.782 (95% CI: 0.758-0.806) and 0.741 (95% CI: 0.702-0.779)］ (P＜0.001). Benign liver diseases patients with AFP≥20 ng/mL as control group, the AUROCs of combined diagnostic model in the diagnosis of HCC and early HCC with serum levels of AFP≥20 ng/mL were 0.960 (95% CI:0.949~0.972) and 0.945 (95% CI: 0.924~0.964) respectively, which were significantly higher than those of AFP ［0.805 (95% CI:0.773~0.837) and 0.734 (95% CI:0.673~0.795)］ (P＜0.001). Conclusion The combined diagnostic model is suitable for HCC diagnosis, especially in the diagnosis of HCC and early HCC with serum level of AFP ≥ 20 ng/ml, the diagnostic value can be improved greatly.