This paper investigates the compression behavior of unsaturated clay under mean stresses up to 160 MPa and different drainage conditions. A new isotropic pressure cell was developed that incorporates matric suction control using the axistranslation technique, and a high-pressure syringe pump operated in displacement-control mode was used to control the total stress and track specimen volume changes. In addition to presenting results from characterization tests on the cell, results from a series of isotropic compression tests performed on compacted clay specimens under drained and undrained conditions are presented. These results permit evaluation of the hardening mechanisms and transition points in the compression curve with increasing effective stress. As expected, specimens tested under undrained conditions were much stiffer than those tested under drained conditions. In the drained tests, the rate of compression was sufficient to permit steady-state dissipation of excess pore-water pressure except under the highest stress ranges. Suction-induced hardening was observed when comparing saturated and unsaturated specimens tested in the drained compression tests. In both the drained and undrained compression tests, the range of applied stresses was sufficient to cause collapse or dissolution of the air voids (pressurized saturation) and convergence of the virgin compression lines for unsaturated specimens with that measured for saturated specimens. A gradual transition to full-void closure was observed at high stresses when the compression curves were plotted on a natural scale, but the shapes of the compression curves at high stresses were not consistent with conventional soil mechanics models when plotted on a semilogarithmic scale. The results from this study provide insight into how constitutive models for unsaturated soils can be extended to high stress conditions for drained and undrained conditions.