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A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinical, demographic, and biochemical data, and we performed a genotyping analysis for common variants previously associated with liver disease risk (HSD17B13 rs72613567:TA and PNPLA3 rs738409). Patients homozygous for the TA allele showed a higher MELD score (p = 0.047), Child−Turcotte−Pugh score (p = 0.014), and INR levels (p = 0.046), as well as decreased albumin (p = 0.004) at baseline. After multivariate analysis, patients with the “protective” variant indeed had an increased risk of hepatic decompensation [aHR 2.37 (1.09−5.06); p = 0.029] and liver-related mortality [aHR 2.32 (1.20−4.46); p = 0.012]. Specifically, these patients had an increased risk of developing ascites (Log-R 11.6; p < 0.001), hepatic encephalopathy (Log-R 10.2; p < 0.01), and higher mortality (Log-R 14.1; p < 0.001) at 5 years of follow-up. Interactions with the etiology of the cirrhosis and with the variant rs738409 in PNPLA3 are also described. These findings suggest that the variant rs72613567:TA in HSD17B13 has no protective effect, but indeed increases the risk of decompensation and death in patients with advanced chronic liver disease., The research leading to these results received funding from Consejería de Salud de la Junta de Andalucía under grant agreements PE-0451-2018 and P20_01075 del programa PAIDI 2020 and from Instituto de Salud Carlos III, Ministerio de Ciencia y Competitividad under grant agreements PI19/01404 and PI19/00589. This research was also funded by European project LITMUS 777377 from Horizon 2020; a contract with fellowships from Consejería de Salud y Familias, Junta de Andalucía, supporting Antonio Gil-Gómez (RH-122-2020) and Angela Rojas (RH-002-2021); grant agreements PFIS FI20/00201 and IFI18/00041 from Instituto de Salud Carlos III to support Sheila Gato and Rocio Montero-Vallejo; and by support from Talento Doctores (PID Junta Andalucía, DOC_00866) to Rocío Muñoz-Hernández.