This RCT evaluated the effectiveness of Eleutherococcus senticosus (Siberian ginseng) for chronic fatigue. Potential subjects were required to have substantial fatigue for more than 6 months with no identifiable cause. The mean change in a fatigue measure was compared for placebo and E. senticosus at 1 and 2 months. Comparisons were for all subjects and for subjects with characteristics previously identified in the literature as important for categorising chronic fatigue. Of the 96 subjects who were randomised to treatment groups, 76 provided information at 2 months of follow-up. Fatigue among subjects assigned to either placebo or E. senticosus was substantially reduced during the study, but differences between treatment groups were not statistically significant in the full sample. Fatigue severity and duration had a statistically significant interaction with response E. senticosus at the P < 0.05 level. Treatment was effective at 2 months for 45 subjects with less severe fatigue and for 41 subjects with fatigue for ≥ 5 years.