The effects of hypoxanthine (HX) and xanthine oxidase (XO) on the (3H)-dopamine (DA) uptake into synaptosomes of rat striatum were examined. Preincubation with 20 mU XO and 0.25 mM HX for 10 min diminished the uptake to 55% of controls. Under these conditions no increase of TBARS as an indicator of lipid peroxidation was observed. Kinetic studies revealed that the decrease in DA uptake was related to the high-affinity transport whereas the low-affinity transport carrier remained unaffected. SOD did not influence uptake inhibition, Catalase completely restituted DA uptake at an activity of 50 U. Thus, hydrogen peroxide and the hydroxyl radical appears to be involved in the deleterious action of HX/XO. The effects of this radical generating system seems to be directed to specific sites of biological membranes.