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Background: The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile., Aims: To investigate the effects of the NAFLD risk alleles on the all-cause and cause-specific mortality in 5581 Chinese adults., Methods: The genome-wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data., Results: Genome-wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P = 8.6 × 10 -7 ). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29 425.1 person-years of follow-up, the overall mortality was 816 per 100 000 person-years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver-specific mortality (P for trend = 0.034) but reduced cardiovascular mortality (P for trend = 0.047). A composite genetic-predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver-specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver-specific mortality were found (P interaction  < 0.05). The reduced serum VLDL1 concentration was responsible for the increased liver-specific mortality related to NAFLD risk alleles., Conclusion: The PNPLA3 rs738409 C>G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver-specific mortality but reduce cardiovascular mortality in overweight/obese Chinese., (© 2022 John Wiley & Sons Ltd.)