Magnesium has been suggested to have anti-inflammatory properties in short-term, mostly in vitro studies. To examine the effect of dietary magnesium modifications in arthritis severity and joint damage DA rats were placed on one of three diet regimens before the induction of autoimmune pristane-induced arthritis (PIA): a 4 wk low-magnesium diet, normal diet, and a magnesium-supplemented diet. The diets were switched to a normal diet 14 days after the induction of PIA (typical time of disease onset). Arthritis severity was scored for 38 days, and joints were examined by histology and quantitative PCR for proinflammatory genes. Rats on the low-magnesium diet were significantly and reproducibly protected and had 70% lower median arthritis severity score, with preservation of normal joint histology without erosive changes. Rats on the normal or magnesium- supplemented diets were not protected and developed equally severe and erosive disease. While the dietary modifications were at disease onset (day 14 postinduction), the protective effect of the short-term low-magnesium diet persisted, suggesting a lasting effect on a critical pathogenic pathway. Rats on the low-magnesium diet had significant reduction in synovial tissue expression of IL-6, RORA, and RORC, which are genes required for the development of Th17 T cells. This study revealed a novel role for dietary magnesium in the regulation of autoimmune arthritis and opens new possibilities for the treatment of autoimmune diseases such as rheumatoid arthritis and psoriatic arthritis with short courses of dietary or drug-induced modulations of magnesium levels.