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Objectives: We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development., Methods: Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo., Results: Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development., Conclusions: A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA., Competing Interests: Competing interests: PPT is a former employee and DMG a current employee of GlaxoSmithKline, UK. GlaxoSmithKline was not involved in the design and/or execution of the study. NdV reports grants from AbbVie, Janssen Biologics, Ergomed Clinical Research, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Roche, as well as personal fees from MSD, UCB, Janssen, non-financial support from Roche, personal fees and non-financial support from Pfizer, all outside the submitted work. In addition, NdV has a patent method for determining the risk of developing arthritis pending. MS reports a research grant from AstraZeneca (received in August 2015). AstraZeneca was not involved in this study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)