Purpose: The prevalence of RLS is close to 10% in the general population, which adversely affects the quality of life (QOL). Exact etiology of RLS is still unknown. Iron deficiency, small intestinal bacterial overgrowth (SIBO), and inflammatory bowel disease (IBD) have clear associations with RLS. Decompensated cirrhosis with portal hypertension has multi-organ involvement, causing minimal and overt encephalopathy, sleep disturbances (dysnomia, parasomnia), and stupor, all of which have a clear association with sub-acute bacterial peritonitis (SBP), which has a precipitating clinical state along with SIBO. This clinical study evaluates the association of RLS in HE amongst decompensated cirrhotics. Methods: One hundred eight (n=108) patients were recruited and subdivided into three sub-groups: Group A (n=36) - decompensated cirrhotic (mean MELD of 16, OHE 20/36 [55%], MHE 16/36 [44%], esophageal varices grade II 24/36 [67%]). Group B (n=36) - chronic liver disease without cirrhosis with mean MELD 6, alcohol-related 9/36 (25%), NASH 12/36 (33%), HCV 12/36 (33%), HBV 1/36 (3%), and AIH 2/36 (6%). Group C (n=36) - healthy controls. Initially, all received Xifaxan, 550 mg orally, twice daily for 10 days, to eradicate co-existing SIBO. All underwent methane breath test for SIBO. Baseline labs: Serum levels for renal function, ferritin, iron studies, hemoglobin and hematocrit, ammonia, celiac and IBD serology, stool lactoferrin and calprotectin, and urine for toxicology screening were collected. Groups A and B underwent neuro-psychometric and flicker testing for MHE and OHE, and sleep testing for RLS (with Mayo RLS questionnaire). Exclusion: Chronic iron deficiency, celiac disease, IBD, major depression, IBS, benzodiazepines, narcotics, alcohol, anti-psychotics, and use of illicit drugs. Results: Group A: 24/36 (67%), had RLS [OHE 16/20 (80%), MHE 8/16 (50%), esophageal varices 8/10 (80%), alcoholic cirrhotic 10/14 (71%), CHC 3/6 (50%), NASH 3/6 (50%), and SIBO 14/36 (39%)]. Group B: 1/36 (3%), RLS and SIBO 7/36 (19%). Group C: 2/36 (6%), RLS and SIBO 3/36 (8%). All individuals were confirmed by sleep study and RLS questionnaire. Serum ammonia has no impact on RLS. Conclusion: This clinical trial postulates that decompensated cirrhotics with hepatic encephalopathy have high incidence of RLS with portal hypertension. Larger trials will validate this finding.