In this study, we investigated the depth-dependent metabolic and structural responses of adult articular cartilage to large-strain, static, unconfined compression. Changes in cell biosynthetic activity and several morphometry-based structural parameters (cell density, cell volume fraction, cell surface-area density, mean cell surface area, and mean cell volume) were measured at eight sites representing different depth-zones between the articular surface and the cartilage/bone border. In addition, local axial strain in the superficial, transitional, upper radial, and lower radial zones was estimated on the basis of the change in cell density values. Static compression of articular cartilage revealed a highly heterogeneous deformation profile through the depth of the sample as well as zone-specific changes in biosynthetic activity, as reflected by incorporation of [³H]proline. The axial strains in the top layers were greater than the applied surface-to-surface strain, whereas axial strains adjacent to the cartilage/bone border were significantly less than the applied strain. Zonal changes in cell density and axial strain that occurred during static compression correlated well with alterations in metabolic activity. These coordinated changes between cell biosynthesis and cartilage structure suggest that zone-specific variations in mechanical stimuli could be responsible for spatially varied patterns of cartilage metabolic activity under load.