Disc degeneration is a chronic remodeling process that results in alterations of matrix composition and decreased cellularity. This study tested the hypothesis that dynamic mechanical forces are important regulators in vivo of disc cellularity and matrix synthesis. A murine model of dynamic loading was developed that used an external loading device to cyclically compress a single disc in the tail. Loads alternated at a 50% duty cycle between 0 MPa and one of two peak stresses (0.9 or 1.3 MPa) at one of two frequencies (0.1 or 0.01 Hz) for 6 h per day for 7 days. An additional group received static compression at 1.3 MPa for 3 h/day for 7 days. A control group wore the device with no loading. Sections of treated discs were analyzed for morphology, proteoglycan content, apoptosis, cell areal density, and aggrecan and collagen II gene expression. Dynamic loading induced differential effects that depended on frequency and stress. No significant changes to morphology, proteoglycan content or cell death were found after loading at 0.9 MPa, 0.1 Hz. Loading at lower frequency and/or higher stress increased proteoglycan content, matrix gene expression and cell death. The results have implications in the prevention of intervertebral disc degeneration, suggesting that loading conditions may be optimized to promote maintenance of normal structure and function.