Genetic variants including PNPLA3-rs738409 C>G, TM6SF2-rs58542926 C>T, MBOAT7-rs641738 C>T, and HSD17B13-rs72613567 T>TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.