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Genetic defects in NOX2 lead to opportunistic infections and inflammatory manifestations such as granulomas in humans, also known as chronic granulomatous disease (CGD). This condition is mirrored in mice with defective ROS production and interestingly both species are predisposed to autoimmune diseases. An unresolved question is whether the hyper\u2010inflammation and tendency to develop autoimmunity are secondary to the increased infections, or whether these are parallel phenomena. We generated germ\u2010free ROS deficient Ncf1 mutant mice that when reared in specific pathogen\u2010free condition, are highly susceptible to collagen\u2010induced arthritis compared with wild\u2010type mice. Strikingly, arthritis incidence and severity was almost identical in germ\u2010free and specific pathogen\u2010free ROS\u2010deficient mice. In addition, partial reduction of the microbial flora by antibiotics treatment did not alter the disease course. 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