Three-dimensional myocardial perfusion imaging requires significant acceleration of data acquisition to achieve whole-heart coverage with adequate spatial and temporal resolution. The present article introduces a compartment-based k-t principal component analysis reconstruction approach, which permits three-dimensional perfusion imaging at 10-fold nominal acceleration. Using numerical simulations, it is shown that the compartment-based method results in accurate representations of dynamic signal intensity changes with significant improvements of temporal fidelity in comparison to conventional k-t principal component analysis reconstructions. Comparison of the two methods based on rest and stress three-dimensional perfusion data acquired with 2.3 × 2.3 × 10 mm(3) during a 225 msec acquisition window in patients confirms the findings and demonstrates the potential of compartment-based k-t principal component analysis for highly accelerated three-dimensional perfusion imaging. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.