This report describes the use of counterimmunoelectrophoresis (CIE) as a method of detecting activation of the complement system. With this technique small amounts of C3 split products (C3c/d) can be detected in plasma samples by specific precipitation with antiserum in less than two hours. The CIE technique is a highly sensitive and rapid method for detecting activation of the complement system in the presence of normal concentration of C3 measured hemolytically or by radial immunodiffusion (RID) in human disease. A clinical investigation was carried out in 40 patients with some systemic rheumatic diseases and 116 normal healthy individuals. The following observations were made: a) plasma and serum from the normal invididuals showed a normal total complement hemolytic activity (CH50), hemolytic active C4 (C4H50) and C3 (C3H50); b) in 30% of the serum samples, it was possible to identify the presence of C3 split products in contrast to only 2.5% of the plasma samples obtained simultaneously; and c) in the patients that showed disease activity, C3 split products were identified by CIE in all cases except one in the presence of normal C3 protein measured by RID.