Antibodies to beta 2-microglobulin (anti-beta 2-mu) were isolated from sera of 6 patients with systemic lupus erythematosus (SLE) and 6 patients with ankylosing spondylitis (AS) by affinity chromatography on beta 2-mu-Sepharose. Specificity of the purified anti-beta 2-mu antibodies was demonstrated by immunofluorescent reactivity with cell surface beta 2-mu and by reactivity with purified beta 2-mu in ELISA. Anti-beta 2-mu from both SLE and AS patients inhibited Concanavalin A and phyto hemagglutinin induced proliferation of normal human peripheral blood lymphocytes (PBL) in a concentration dependent manner. High concentrations of anti-beta 2-mu inhibited pokeweed mitogen (PWM) induced PBL proliferation whereas lower concentrations enhanced the PWM response. Anti-beta 2-mu also inhibited E-rosette formation. The inhibition and enhancement of mitogen induced PBL proliferation and the inhibition of E-rosette formation were reversed when the antibodies were preincubated with purified beta 2-mu.