Summary Background and aim: Lactulose is considered first-line therapy for hepatic encephalopathy (HE). However, the effect of adherence with lactulose on recurrence of HE outside of clinical trials is unclear. Methods: Patients with cirrhosis who were initiated on lactulose after an index HE episode in a liver-transplant center were retrospectively reviewed. Recurrence of HE, precipitating factors and adherence on lactulose, were investigated using chart review and electronic pharmacy records. Patients with/without HE recurrence were compared and predictors of recurrence were analyzed. Results: 137 patients with cirrhosis(age 55+/-6years, MELD 17+/-7) who were initiated on lactulose after the index HE episode were included. 103 patients developed recurrent HE 9+/-1 months after their index episode;39(38%) of these were not adherent on lactulose, 56(54%) were adherent and 8(8%) had lactulose-associated dehydration leading to recurrence. Recurrent HE precipitants in lactulose-adherent patients were sepsis(19%), GI bleeding(15%), hyponatremia(4%) and TIPS (7%). Overall, all patients who did not suffer recurrence were adherent on lactulose. In contrast, the adherence rate for those who recurred was only 64% (p=0.00001).On multivariate regression, lactulose non-adherence (OR 3.26) and MELD score (OR 1.14) were the factors that predicted recurrence. Conclusions: Lactulose non-adherence and lactulose-associated dehydration were associated with nearly half of recurrent HE episodes.