Background This RCT compared non-surgical treatment of peri-implant mucositis with or without systemic antibiotics. Materials and Methods Forty-eight subjects received non-surgical debridement with or without systemic Azithromax ® (4 days), and were followed during 6 months. The checkerboard DNA-DNA hybridization method was used to analyse the microbiological material. Results Five subjects were excluded due to antibiotic medication during follow-up. At baseline,1 and 3 months no group differences were found. Statistical analysis failed to demonstrate differences in probing pocket depths (PPD) values at 6 months (Mean diff PPD: 0.5 mm, SE: ±0.4 mm, 95% CI: −0.2, 1.3, p = 0.16). Mean% implant bleeding decreased between baseline and month 6 from 82.6% to 27.3% in the test, and from 80.0% to 47.5% in the control group (p < 0.02). Throughout the study, no study group differences in bacterial counts were found. Conclusion No short-term differences were found between study groups. The clinical improvements observed at 6 months may be attributed to improvements in oral hygiene. The present study does not provide evidence for the use of systemic antibiotics in treatment of peri-implant mucositis.