Summary Background  Transcatheter arterial chemoembolization (TACE) has been limited in palliative treatment of unresectable hepatocellular carcinoma (HCC) with major portal vein (PV) invasion due to the possibility of liver failure following embolization. Transcatheter arterial chemoinfusion (TACI) has been an option in such cases. Aim  To compare clinical outcomes after TACE vs. TACI in HCC patients with major PV occlusion. Methods  We compared clinical outcomes after TACE vs. TACI in HCC patients with major PV occlusion. From 2005 to 2007, 110 HCC patients with major PV thrombosis were treated with TACE (n = 49) or TACI (n = 61). Results  The morbidity rate was similar for both TACE (6.1%) and TACI (6.5%) patients, and complications were adequately managed using medical treatment. The Kaplan–Meier survival analysis showed that the survival period was significantly longer for the TACE group (median: 14.9 months) than for the TACI (median: 4.4 months) group (P < 0.001). There was a higher probability of death in the TACI group than in the TACE group in both our multivariate Cox‐proportional hazards (OR 3.09, P < 0.001) and the propensity score‐matched (27 pairs) cohort analyses (OR 2.27, P = 0.024). Conclusions  Transcatheter arterial chemoembolization can be safely performed in HCC patients with main PV occlusion. Compared with TACI, TACE may result in longer survival of HCC patients with major PV occlusion.