Background/Aims: L-carnitine is potentially beneficial in patients with hepatic encephalopathy (HE). We aimed to evaluate the impact of L-carnitine on the quality of life and liver function in patients with liver cirrhosis and covert HE.Methods: We conducted an investigator-initiated, prospective, multi-center, double- blind, randomized phase III trial in patients with covert HE. A total of 150 patients were randomized 1:1 to L-carnitine (2 g/day) or placebo for 24 weeks. Changes in quality of life and liver function were assessed at 6 months. The model for end-stage liver disease (MELD), the 36-Item Short Form Survey (SF-36), the psychometric hepatic encephalopathy score (PHES), and the Stroop Test were evaluated in all patients.Results: The total SF-36 score significantly improved in the L-carnitine group after 24 weeks (difference: median, 2; interquartile range, 0 to 11; <i>p</i> < 0.001); however, these values were comparable between the two groups. Furthermore, there was a significant ordinal improvement in PHES scores among patients with minimal HE who were in the L-carnitine group (<i>p</i> = 0.007). Changes in the total carnitine level also positively correlated with improvements in the Stroop test in the L-carnitine group (color test, <i>r</i> = 0.3; word test, <i>r</i> = 0.4; inhibition test, <i>r</i> = 0.5; inhibition/switching test, <i>r</i> = 0.3; all <i>p</i> < 0.05). Nevertheless, the MELD scores at week 24 did not differ between the groups.Conclusions: Twenty-four weeks of L-carnitine supplementation was safe but ineffective in improving quality of life and liver function.