Prolactin (PL) is essential for the normal function of the immune system. It is required for the induction of a number of autoimmune conditions in experimental animals. The role of prolactin in the immunopathogenesis of autoimmune human disease has not been established. RA is characterized by a variety of immune and inflammatory processes which determine disease activity. It has a pronounced diurnal periodicity with a peak at 03.15 hours. Since PL has a diurnal rhythm of secretion in man with a peak at about 02.00 hours, it may contribute to the nocturnal worsening of RA. We show that patients with RA secrete an excess of prolactin as evidenced by an upregulated diurnal periodicity and an abnormal increase in plasma prolactin concentration following surgery. By contrast, patients with chronic osteomyelitis, who had chronic inflammation of similar severity to patients with RA, had a normal prolactin diurnal rhythm and response to surgery. Hence, the abnormal changes in prolactin physiology seen in RA appear to be a feature of the disease per se rather than related to chronic inflammation. The elevated levels of prolactin may contribute to disease activity by augmenting immune processes and may be an additional genetic factor, independent of HLA-DR4, in the immunopathogenesis of RA. Furthermore, the effective inhibition of prolactin secretion and/or action may have potential as therapy for RA.