The purpose was to evaluate rifaximin antibiotic therapy for restless legs syndrome (RLS) patients who have small intestinal bacterial overgrowth (SIBO). Patients with RLS were recruited by advertisements and were included if they met all international RLS criteria and had an international RLS (IRLS) score ≥15. Patients were excluded if they had secondary RLS or disorders other than irritable bowel syndrome that are associated with SIBO. Patients and healthy controls were screened for SIBO using lactulose breath tests. Patients with SIBO were randomized to receive rifaximin 1650 mg daily (n= 20) or placebo (n= 10) for 10 days. Global RLS and IRLS scores were assessed over 25 days. In IRLS responders (i.e. patients with improvement in IRLS scores), mean IRLS score improvement on day 11 was significantly greater for rifaximin (−6.0 ± 5.0) versus placebo (1.7 ± 5.1; P= 0.017). Results on day 18 showed numerical improvement with rifaximin compared with placebo (−7.8 ± 5.1 vs−0.33 ± 10; P= 0.058). Rifaximin improved IRLS scores for all 20 patients from baseline to days 11 (P= 0.037) and 18 (P= 0.006) compared with the placebo group, which had no significant improvement from baseline. Marked and moderate global improvement of RLS symptoms occurred in 40% and 22% of patients in the rifaximin and placebo groups, respectively. Short‐term rifaximin improved RLS symptoms; however, more aggressive SIBO therapy (as previously reported) and a higher powered study is required to further define the efficacy of antibiotic treatment of RLS.