Background: Nonalcoholic fatty liver disease (NAFLD) is a significant epidemiological problem with rising prevalence. Due to limited literature, the objective of this study is to examine the association between polypharmacy and health related quality of life (QoL) in NAFLD adult patients. Methods: Retrospective observational study design to analyze baseline data conducted by Steatohepatitis Clinical Research Network (NASH CRN). Patients were classified as receiving a polypharmacy therapy with five or more medications in their first screening visit. Quality of Life was measured using the Short Form 36 (SF-36) instrument. Each patient self-reported the SF-36 form during the screening visit was compared between polypharmacy and non-polypharmacy groups using Wilcoxon Rank Sum test. Multivariable generalized linear models and multinomial logistic regression were performed to examine each predictor and its effect on QoL. Results: Data included 1067 NAFLD adult patients; 834 patients used polypharmacy. The mean age was 48.64 years, and most patients were female (62%). Comparing NAFLD patients without steatohepatitis, borderline NASH, and definite NASH, the non-polypharmacy group had a significantly higher QoL than the polypharmacy group in Physical Component Summary (PCS) (86.25 vs 66.88, 85 vs 67.5, and 79.375 vs 63.12 respectively, all p-values < 0.01) and Mental Component Summary (MCS) (83.5 vs 73.38, 78.75 vs 67.62, and 78.75 vs 70.65 respectively, all p-values < 0.01). Discussion & Conclusion: Adults diagnosed with NAFLD with polypharmacy have lower QoL than adults diagnosed with NAFLD without polypharmacy. Number of medications had a significant negative impact on PCS, MCS, and all SF-36 domains except mental health, role physical limitation and role emotional limitation domains. Other factors that affect QoL negatively in NAFLD adult patients are female gender, obesity, diabetes, depression, and unemployment. Higher income had favorable effect on QoL.