Addition of cysteine protease inhibitors to cells ex pressing amyloid precursor protein (APP) resulted in a >2-fold increase in appearance of the secreted extracellular domain of APP in the media. This was accounted for by increased flux of APP into the secretory pathway since protease inhibitors also caused a two-fold increase in newly translated, incompletely glycosylated APP detected by pulse-labeling. These results show that a portion of newly translated APP molecules are normally rapidly degraded by cysteine protease(s) but can enter the secretory pathway when degradation is inhibited. Newly translated APP molecules are thus still competent for posttranslational processing in distal cellular compartments. Their degradation thus may not result from misfolding but merely susceptibility to an endoplasmic reticulum localized cysteine protease.