Maximum-likelihood (ML) estimation has very desirable properties for reconstructing 3D volumes from noisy cryo-EM images of single macromolecular particles. Current implementations of ML estimation make use of the Expectation-Maximization (EM) algorithm or its variants. However, the EM algorithm is notoriously computation-intensive, as it involves integrals over all orientations and positions for each particle image. We present a strategy to speedup the EM algorithm using domain reduction. Domain reduction uses a coarse grid to evaluate regions in the integration domain that contribute most to the integral. The integral is evaluated with a fine grid in these regions. In the simulations reported in this paper, domain reduction gives speedups which exceed a factor of 10 in early iterations and which exceed a factor of 60 in terminal iterations. (C) 2010 Elsevier Inc. All rights reserved.