Cerebral deposition of β-amyloid (Aβ) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein γ-secretase complex generates Aβ. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of γ-secretase and that the levels of secreted Aβ inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral γ-secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Aβ levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Aβ production in an in vitro γ-secretase assay. Consistent with an extracellular source that modulates Aβ metabolism, synthetic Aβ was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on ε-site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Aβ levels not by regulating γ-secretase activity, but by stimulating extracellular degradation of Aβ. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Aβ levels by an indirect mechanism involving MMPs that can degrade extracellular Aβ.