Ganoderma lucidum has been widely used to treat various diseases, including cancer, diabetes, and neurasthenia in many Asian countries. This randomized, double-blind, placebo-controlled parallel study aimed to investigate the efficacy and safety of a polysaccharide extract of G. lucidum (Ganopoly) in Chinese patients with neurasthenia. One hundred thirty-two patients with neurasthenia according to the diagnosis criteria of the 10th International Classification of Diseases were included in this study. Written consents were obtained from the patients, and the study was conducted in accordance with Good Clinical Practice guidelines. Patients were randomized to receive Ganopoly or placebo orally at 1,800 mg three times a day for 8 weeks. Efficacy assessments comprised the Clinical Global Impression (CGI) improvement of severity scale and the Visual Analogues Scales for the sense of fatigue and well-being. In 123 assessable patients in two treatment groups at the end of the study, Ganopoly treatment for 8 weeks resulted in significantly lower scores after 8 weeks in the CGI severity score and sense of fatigue, with a respective reduction of 15.5% and 28.3% from baseline, whereas the reductions in the placebo group were 4.9% and 20.1%, respectively. The score at day 56 in the sense of well-being increased from baseline to 38.7% in the Ganopoly group compared with 29.7% in the placebo group. The distribution of the five possible outcomes from very much improved to minimally worse was significantly different (X (2) = 10.55; df = 4; P = .0322) after treatment with Ganopoly or placebo. There was a percentage of 51.6% (32 of 62) in the Ganopoly group rated as more than minimally improved compared with 24.6% (15 of 61) in the placebo group (X (2) = 9.51; df = 1; P = .002). Ganopoly was well tolerated in the study patients. These findings indicated that Ganopoly was significantly superior to placebo with respect to the clinical improvement of symptoms in neurasthenia.