Background <p>Recent studies have shown that unhealthy sleep behaviors are associated with chronic liver disease. However, the association of sleep patterns and genetic susceptibility with the incidence of cirrhosis remains inadequately elucidated.</p> Methods <p>This study included 364,308 participants initially free of liver cirrhosis from the UK Biobank. Sleep patterns were derived based on five self-reported sleep behaviors, including sleep duration, chronotypes, insomnia, snoring, and daytime sleepiness. Additionally, a polygenic risk score for cirrhosis was constructed for each participant. Cox regression models were utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) of cirrhosis associated with sleep patterns and polygenic risk score.</p> Results <p>During a median follow-up of 12.6 years, we recorded 1,814 cirrhosis events. Compared with healthy sleep patterns, the HRs (95% CI) for moderate and poor sleep patterns were 1.27 (95% CI: 1.14–1.42) and 1.73 (95% CI: 1.45–2.08), respectively. A joint effect of sleep and genetic factors on cirrhosis risk was observed, with HR reaching 3.50 (95% CI: 2.42–5.06) with poor sleep patterns and high genetic risk compared with those with healthy sleep patterns and low genetic risk. In addition, the high genetic risk for participants, poor sleep patterns of standardized decade liver cirrhosis were 0.49%, as opposed to 0.30% for those with healthy sleep patterns. The same trend was witnessed in individuals at low genetic risk.</p> Conclusions <p>Our results show that the healthy sleep patterns are associated with a lower risk of incident liver cirrhosis, especially in individuals with high genetic susceptibility.</p>