Background In recent years, levocarnitine has been reported to be an effective treatment in patients with liver cirrhosis, but its mechanism is not fully understood. In the present study, we prospectively examined the efficacy of levocarnitine in relieving symptoms of fatigue in patients with cirrhosis but without overt hepatic encephalopathy. Methods Twenty-one cirrhotic patients who were able to undergo fatigue symptom evaluations at our institution were enrolled. A total of 12 cirrhotic patients underwent levocarnitine treatment (1200-1800 mg/day), and 9 patients did not undergo levocarnitine treatment. Patient age, sex, and Child–Pugh (C-P) class, complications and the etiology of cirrhosis were assessed. As primary end-points, we investigated whether the levocarnitine treatment exerted any beneficial effects by assessing the symptoms of fatigue [8-item Short-Form Health Survey (SF-8) and Fisk Fatigue Severity Scores (FFSSs)] at baseline and 3 months after treatment. Furthermore, as exploratory secondary end-points, we investigated whether the levocarnitine treatment exerted effects on ameliorating oxidative stress by assessing the serum thioredoxin (TRX) and urinary 8-hydroxydeoxyguanosine (8-OhdG) levels. Results The median age of the patients was 73 years. Three males and 18 females had C-P classes A and B (14 and 7 patients, respectively), and 3 patients (14.3%) had a history of hepatocellular carcinoma treatment. A total of 6 cases of diabetes (28.6%), 6 cases of ascites (28.6%), and 4 cases of varices (19.0%) were identified. There were no significant differences in the clinical laboratory values between the two groups. The FFSS and SF-8 scores were significantly improved in the patients with cirrhosis who underwent levocarnitine treatment ( P <0.01) but not in patients who did not undergo levocarnitine treatment. Furthermore, three months after the levocarnitine treatment, the serum carnitine concentrations were significantly increased and the serum thioredoxin levels were decreased in the patients with cirrhosis who underwent levocarnitine treatment ( P <0.005). Conclusion These results suggest that levocarnitine treatment may relieve symptoms of fatigue in cirrhotic patients by reducing oxidative stress.