The purpose of this study was to investigate whether clinical improvement in patient with rheumatoid arthritis (RA) taking oral Bovine type II collagen (bCII) is associated with changes in levels of anti-bCII total IgG antibody and its subclasses. Four groups were given either 5, 0.5 or 0.05 mg of bCII or a placebo in a double-blind randomised control trial. The sera IgG anti-collagen type II and antibodies of the IgG subclasses, IgG1-4, were measured at the start and end of the trial by ELISA. Total IgG anti-collagen II antibodies in the pooled active treatment groups were statistically significantly reduced compared with the placebo group (p = 0.021). Decreasing total IgG titres were observed in the 0.5-mg group (p = 0.008), 0.05-mg group (p = 0.004) and 5-mg group (p = 0.078) before and after treatment. For IgG1, IgG2, IgG3 and IgG4 subclasses, in the 0.5-mg group in which the best clinical response was observed, there was statistically significant decreases observed in the IgG2 and IgG3 subclasses (p = 0.047, p = 0.046). Treatment with bCII in patients with RA led to a reduction in anti-collagen II antibody titre indicating an active biological effect as observed previously in animal model of RA. The largest decrease in total and subclasses of anti-collagen antibody titres occurred in the groups of patients with the best therapeutic response to bCII, supporting the conclusion of the clinical trial and suggests that immune regulation explains the therapeutic effect.