We investigated peripheral-blood mononuclear cell (PBMC) response to immunosuppressive drugs and its influence on glucocorticoid therapy in ulcerative colitis (UC). IC50s of immunosuppressive drugs on in vitro blastogenesis of PBMCs stimulated with concanavalin A were estimated in 76 UC and 146 healthy subjects. Individual differences in IC50s for prednisolone, methylprednisolone, cyclosporine, and tacrolimus on blastogenesis of PBMCs from UC patients were spread from 11.0 to 1000, 0.6 to 1000, 0.01 to 1000, and 0.001 to 4.6 ng/ml, respectively. Normal upper thresholds for IC50s of these drugs were estimated from the mean + 2 S.D. of the IC50s of healthy PBMCs, and the patients exhibiting IC50s over these levels were arbitrarily considered as resistant. The incidences of resistance to glucocorticoids and cyclosporine in UC were significantly higher than those in healthy subjects (p < 0.0005). In 14 UC patients, there was a significant correlation between amounts of prednisolone (p < 0.05) or period of prednisolone administration (p < 0.05) for UC treatment and prednisolone IC50. The results showed that large individual deviations in PBMC response to the drugs were observed in UC, and UC patients exhibiting low PBMC sensitivity to prednisolone required a high prednisolone amount as well as long period of prednisolone administration for treatment. Thus, the drug sensitivity tests could be informative to single out refractory patients to the immunosuppressive therapy.