Recent reports suggest that certain Ca2+-channel-blocking drugs reduce the severity of atherosclerosis in cholesterol-fed animals. To determine whether the suppression of atherogenesis is related to altered lipoprotein metabolism, we have assessed the effects of these drugs on the catabolism of plasma low density lipoproteins (LDL) by human skin fibroblasts. The Ca2+-channel-blocking drugs verapamil and diltiazem inhibit the lysosomal degradation of LDL by these cells; degradation of epidermal growth factor was also inhibited by the same drugs, suggesting a general effect of these drugs on lysosomal function. In contrast, nifedipine did not affect the degradation of LDL or epidermal growth factor. None of the drugs affected phospholipid or protein synthesis. Entry of LDL into the lysosomes also was not affected. [3H]Diltiazem, which inhibited LDL degradation, accumulated in the lysosome-rich fraction, whereas [3H]nimodipine, a drug structurally and functionally similar to nifedipine, did not accumulate. We suggest that the inhibitory effect of some of the Ca2+-channel-blocking drugs on lysosomal function is due to their basic nature, causing them to accumulate in lysosomes, thereby increasing intralysosomal pH.