Rheumatoid arthritis (RA) is a chronic joint disease of undetermined cause that is associated with significant disability. Low-grade fever, anemia, and weight loss are recognized extra-articular features associated with increased disease activity. Weight loss and cachexia are well-established features of RA. The mechanism behind weight loss in RA is not known and may be multifactorial. Reduced energy intake and hypermetabolism are the major two factors frequently implicated in the etiology of RA cachexia. One would expect the effect of the above two factors to be highest during increased disease activity and lowest during remission. The purpose of this study was: (a) to establish whether in RA patients changes in body composition mirror changes in disease activity, (b) to investigate the relation between the energy expenditures and weight loss, (c) to examine the dietary energy intake and its role in weight loss in RA patients, and (d) to investigate the relation between the cytokine interleukin (IL)-6 and other variables including resting energy expenditure (REE), body composition, and acute phase reactants. Fourteen patients with RA were age-, sex-, and race-matched with 14 controls from patients with noninflammatory diseases/soft tissue rheumatism. The measurements included the following: disease activity assessment, anthropometric measurements, indirect calorimetry, and measurements of dietary intake. Blood was collected to measure the acute-phase reactants and IL-6 levels. We demonstrated that loss of fat-free mass (FFM) might accelerate during times of increased disease activity and is only partially restored during periods of reduced disease activity. This probably means that the extent of cachexia in RA patients is determined by the frequency and intensity of disease activity (flare) for a given disease duration. Hypermetabolism with increased REE was more evident during increased disease activity. Hypermetabolism in the face of increased energy intake continued to cause loss of the FFM. Interleukin-6 correlates with increased REE and erythrocyte sedimentation rate. There was no direct association between IL-6 level and low FFM. We conclude that loss of FFM is common in RA, cytokine production in RA is associated with altered energy metabolism, and preservation of FFM is important in maintaining good quality of life in patients with RA.