Background: Panax ginseng is a well-known immune modulator, and there is concern that its immune-enhancing effects may negatively affect patients with rheumatoid arthritis (RA) by worsening symptoms or increasing the risk of adverse effects from other drugs. In this randomized, crossover clinical trial, we evaluated the impact of Korean Red Ginseng (KRG) on disease activity and safety in RA patients. Methods: A total of 80 female RA patients were randomly assigned to either the KRG (2 g/d, n = 40) treatment or placebo (n = 40) groups for 8 wk, followed by crossover to the other treatment group for an additional 8 wk. The primary outcome was the disease flare rate, defined as worsening disease activity according to the disease activity score 28 joints-erythrocyte sedimentation rate (DAS28-ESR). The secondary outcomes were development of adverse events (AEs) and patient reported outcomes. Outcomes were evaluated at baseline and 8 wk and 16 wk. The outcomes were compared using the Chi-square test. Results: Of the 80 patients, 70 completed the full study. Their mean age was 51.9 yr, and most exhibited low disease activity (mean DAS28-ESR 3.5 ± 1.0) at enrollment. After intervention, the flare rate was 3.7% in each group. During KRG treatment, 10 AEs were reported, while five AEs were developed with placebo; however, this difference was not statistically significant (p = 0.16). Gastrointestinal- and nervous system-related symptoms were frequent in the KRG group. Conclusion: KRG is not significantly associated with either disease flare rate or the rate of AE development in RA patients. Keywords: effect, Korean Red Ginseng, rheumatoid arthritis, safety