Aim The aim of this study is to compare the long-term effect of proton irradiation with that of Lipiodol targeted chemotherapy(L-TAI) for Hepatocellular Carcinoma (HCC). Materials and Methods 48 patients(75 HCC) treated with proton irradiation(mean 75Gy) were analyzed retrospectively. 29 cases(46 lesions) were treated with proton alone(Mono) and 19 cases(29 lesions) also received L-TAI(Combi). The results from these patients were compared with those of 42 cases(65 lesions) treated with L-TAI alone as a historical control, whose background did not differ. All tumors were followed up by CT scan and ultrasonography. Results 1): Size reduction was observed after 1, 2, 4 yrs in 87%(40), 92%(11), 100%(1), respectively, in the Mono group, 72%(21), 100%(10), 100%(3), respectively, in the Combi group, compared with 46%(30), 63%(10), 67%(2), respectively, in the L-TAI group. 2): Local tumor control (no local recurrence) rates of the proton group(Mono and Combi)(93%, 100% at 1, 4 yrs) were significantly higher(p<0.01) than those of the L-TAI group(only 64%, 67% at 1, 4yrs) upon Kaplan and Meier's methods. 3): Survival rate was also significantly higher (P<0.01) in the proton groups than in the L-TAI group. Cummurative survival rates at 2 and 4 yrs were 87%, 74%, respectively, for the proton groups and 74%, 45%, respectively, for the L-TAI group. 4): Excellent QOL was maintained in all cases treated with proton during observation period. Conclusion HCC patients treated with proton irradiation showed superior local tumor control as well as better survival and QOL, in comparison with L-TAI.