Background Despite transarterial chemoembolization (TACE) serving as the first-line treatment for patients with intermediate stage B hepatocellular carcinoma (HCC), complete response rates are generally below 27%. Purpose To compare the efficacy and safety of an anhydrous cisplatin suspension in ethiodized oil-based TACE versus a conventional aqueous cisplatin emulsion in the treatment of participants with HCC. Materials and Methods In this prospective, multicenter, randomized controlled trial conducted from September 2016 to February 2023, participants from three hospitals in Hong Kong were randomized to an experimental or control group in a 1:1 ratio. The experimental group received an anhydrous cisplatin suspension (4 mL of ethiodized oil with 20 mg of cisplatin powder). The control group received a conventional aqueous cisplatin emulsion. TACE was performed within 4 weeks after randomization in two to three treatments, 2 months apart. Response was assessed with CT and digital subtraction angiography during subsequent TACE. Primary end points were complete tumor response and severe adverse events. Secondary end points included progression-free survival and overall survival (OS). Survival outcomes were compared using the log-rank test and hazard ratios with 95% CIs. Results A total of 77 participants were included (median age, 68 years; IQR, 64-75 years; 59 men). At 6 months, the complete tumor response rate was higher in the suspension group (90% [35 of 39 participants]) compared with the emulsion group (47% [18 of 38 participants]; P < .001). Serious adverse events were similar in the suspension group (2.3% [three of 128 procedures]) and emulsion group (5.2% [eight of 153 procedures]; P = .21). Median progression-free survival was higher in the suspension group (21.1 months; 95% CI:14.3, 38.9) compared with the emulsion group (10.4 months; 95% CI: 7.3, 13.4) (hazard ratio, 0.35; P < .001). Median OS was higher in the suspension group (53.3 months; 95% CI: 40.5, not reached) than in the emulsion group (36.0 months; 95% CI: 25.7, 46.6) (hazard ratio, 0.32; P = .004). Conclusion Ethiodized oil-based TACE using an anhydrous cisplatin suspension resulted in better complete tumor response, progression-free survival, and OS rates compared with the conventional aqueous cisplatin emulsion. ClinicalTrials.gov identifier NCT03268499 © RSNA, 2025 Supplemental material is available for this article.