The relationship between the erythrocyte sedimentation rate (ESR) and plasma proteins was studied within homogenous clinical material and in vitro models. In acute phase reactions, fibrinogen was the likely cause of the ESR-elevation, but there were significant associations between the ESR and the concentrations of alpha 1-antitrypsin, C3, haptoglobin and albumin. In chronic diseases, the ESR-elevation was probably caused by fibrinogen, mono- or polyclonal increase of IgG, IgA, IgM alone or in combinations. In multiple myeloma of the IgG and IgA subtypes, significant correlations were found between the ESR and the monoclonal proteins or between the ESR and the percentage of plasma cells in bone marrow. Model studies showed that the ESR increased linearly with the concentrations of fibrinogen or gammaglobulin (IgG) when these exceeded normal thresholds. The ESR was slightly decreased by increasing concentrations of albumin. Albumin had a synergistic effect on the ESR together with gamma-globulin, but not together with fibrinogen.