The plasma proteome of type I Gaucher disease patients was investigated by 2D gel electrophoresis (2DGE). Using the classical procedure with 8 M urea treated plasma, several high molecular weight proteins were absent from Gaucher plasma specimens, while additional low molecular weight proteins were visible. The latter were identified as proteolytic degradation products. Adding small amounts of patient plasma to control plasma gave extensive protein breakdown. The presence of 2.2 M thiourea/7.7 M urea in the rehydration solution totally prevented breakdown. In the 'urea only' solution, protease(s) uniquely present in Gaucher plasma, appear to be still active towards other denatured plasma proteins at low pH. Therapy of patients results in gradual disappearance of proteolytic capacity from plasma specimens, indicating it to be related to the presence of Gaucher storage cells. The proteolytic activity could be partly removed from Gaucher plasma samples by Concanavalin A, suggesting that glycoproteins are involved. Reduction of proteolysis by Pepstatin A and Leupeptin implies that cathepsins, proteases known to be overproduced by Gaucher storage cells, are involved. In conclusion, 2DGE Gaucher plasma proteomes should be interpreted cautiously given the abnormal high levels of proteases associated with this disorder.