This is the first prospectively randomized study of the use of melphalan/prednisone and colchicine in the treatment of primary systemic amyloidosis. One hundred one patients were stratified according to their dominant clinical manifestation. Forty-nine patients initially received melphalan/prednisone and eight subsequently had colchicine added to their regimen. Fifty-two patients initially received colchicine and 35 subsequently required melphalan/prednisone because of progressive disease. There was no difference in survival when the two groups were analyzed in aggregate (melphalan/prednisone, 25.2 months versus colchicine, 18 months; p = 0.23). When the survival of patients receiving only one regimen was analyzed or when survival was analyzed from the time of entry into the study to the time of death or progression of disease, significant differences (p less than 0.001 and p less than 0.0001, respectively) were evident, favoring melphalan/prednisone. This study suggests that melphalan/prednisone is superior to colchicine in the treatment of primary amyloidosis, but to confirm this impression, a study without a crossover group is necessary.