The canonical model of eukaryotic translation posits that efficient translation initiation increases protein expression and mRNA stability. Contrary to this dogma, we show that increasing initiation rate can decrease both protein expression and stability of certain mRNAs in the budding yeast, S. cerevisiae. These mRNAs contain a stretch of poly-basic residues that cause ribosome stalling. Using computational modeling, we predict that the observed decrease in gene expression at high initiation rates occurs when ribosome collisions at stalls stimulate abortive termination of the leading ribosome and cause endonucleolytic mRNA cleavage. We test our prediction by identifying critical roles for the collision-associated quality control factors, Asc1 and Hel2 (RACK1 and ZNF598 in humans, respectively). Remarkably, hundreds of S. cerevisiae mRNAs that contain ribosome-stall sequences also exhibit lower translation efficiency. We propose that these mRNAs have undergone evolutionary selection for inefficient initiation to escape collision-stimulated reduction in gene expression.