T cells produce regulatory cytokines which control inflammation. In rheumatoid arthritis (RA), a Th1 cytokine profile has been described in the synovium. In order to assess the Th1/Th2 cytokine balance in blood, a one step culture-immunoassay procedure was used to measure the ex vivo production of IFN gamma and IL-4 by whole blood cells from 26 RA patients and 25 controls. For comparison, the same cytokines were measured by ELISA in supernatants of activated whole blood cells. The direct whole blood assay was 10-fold more sensitive than standard ELISA to measure IL-4 levels. IL-4 production was higher in RA patients than in controls, whereas that of IFN gamma was lower. Accordingly, the IL-4/IFN gamma ratio, which reflects the Th2/Th1 cytokine balance in blood, was higher in RA patients (P < 0.0001). The present findings indicate a Th2-over-Th1 cytokine balance profile in RA blood. These results are in contrast with the Th1-over-Th2 pattern previously found in the joint, indicating that the two compartments appear to be differently regulated.