BACKGROUND & AIMS: Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) who have achieved sustained virologic response at off-treatment week 12 (SVR12) using direct-acting antivirals (DAAs) for HCV. METHODS: A total of 1,598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC after achieving SVR12. MASLD was defined as presence of controlled attenuation parameter (CAP) ≥248 dB/m and ≥1 cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping. RESULTS: The incidence rate of HCC was 1.44 per 100 person-years of follow-up (95% CI 1.19-1.74). Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p <
0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, liver stiffness measurement, platelet count, and AFP, MASLD (adjusted hazard ratio 2.07
95% CI 1.36-3.16
p <
0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution hazard ratio of 2.07 (95% CI 1.34-3.19, p <
0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development. CONCLUSION: After achieving SVR12, patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect of MASLD on HCC remain crucial for this population. IMPACT AND IMPLICATIONS: The risk of de novo hepatocellular carcinoma (HCC) among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) who have attained a sustained virologic response to direct-acting antivirals remains to be confirmed. In this study, recruiting 1,598 patients in Taiwan, individuals with MASLD had an approximately two-fold increased risk of de novo HCC compared to those without MASLD after achieving a sustained virologic response. MASLD significantly mediated cardiometabolic risk factors for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control cardiometabolic risk factors in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication.