In this paper, design expressions are derived that extend the American Iron and Steel Institute (AISI) direct strength method (DSM) to cold-formed steel columns with holes. For elastic buckling-controlled failures, column capacity is accurately predicted by using existing DSM design equations and the cross-section and global elastic buckling properties calculated including the influence of holes. For column failures in the inelastic regime, in which strength approaches the squash load, limits are imposed to restrict column capacity to that of the net cross section at a hole. The proposed design expressions are validated with a database of existing experiments on cold-formed steel columns with holes, and more than 200 nonlinear finite-element simulations that evaluate the strength prediction equations across a wide range of hole sizes, hole spacings, hole shapes, and column dimensions. The recommended DSM approach is demonstrated to provide a broad improvement in prediction accuracy and generality when compared to the AISI main specification, and, with the recent introduction of simplified methods for calculating elastic buckling properties including the influence of holes, it is ready for implementation in practice.