Thirty-two patients with high and low anti-RNP antibody titers were followed prospectively during a mean observation of 65 months. The following 4 titer patterns were observed: persistently high, low increasing to high, high decreasing to low and persistently low titers. At first admission, 17 of the 23 patients with high anti-RNP titers did not fulfill the criteria of defined connective tissue diseases (CTD). The clinical courses were characterized by the appearance of new organ manifestations and at the end of the study 17/23 fulfilled the criteria for mixed CTD (MCTD). A development towards systemic lupus erythematosus (SLE) was seen in one, concomitant with decreasing anti-RNP titer. None developed symptoms compatible with progressive systemic sclerosis. The 9 patients with a low anti-RNP titer were characterized by a stable clinical course, including 4 with SLE, 2 with Raynaud's phenomenon, and one each with Sjögren's syndrome, discoid lupus erythematosus and rheumatoid arthritis + Sjögren's syndrome. The most frequently occurring clinical manifestations among the patients with MCTD were Raynaud's phenomenon, puffy hands, arthritis, myalgias, and sicca symptoms. Myositis and impaired pulmonary function were also seen, but glomerulonephritis was not. The symptoms were fluctuating and the manifestations clinically different from other well defined CTD. The morbidity was moderate and the mortality low. High anti-RNP titer observed at any time seems associated with a clinical syndrome phenotypically different from other CTD favoring the notion of MCTD being a distinctive clinical syndrome.