A prospective clinical and laboratory study is described which was undertaken to assess the significance of the rheumatoid biologically active factor (RBAF) in 127 patients having rheumatoid arthritis. The RBAF was detected in the serum of 30% of these patients, while it was present in the synovial fluid of 78% of the twenty-three patients in whom synovial fluid was obtained. It was found that persons with the RBAF in their serum showed more advanced changes of rheumatoid disease than persons without the RBAF in their serum. This finding was evident at a statistically significant level in comparisons of grip strength, clinical and X-ray evidence of joint destructive changes, and frequency of extra-articular manifestations of rheumatoid disease. There was no difference between the RBAF-positive and RBAF-negative groups in their erythrocyte sedimentation rates or in clinical signs of articular inflammation. These results suggested that the RBAF correlated with the overall extent of rheumatoid disease rather than with the existing level of rheumatoid inflammatory activity. A continuing assessment of the same group of patients may help to clarify whether the RBAF participates in the pathogenesis of rheumatoid arthritis or is merely a by-product of this disease.