Previous studies have indicated that 6%–30% of newly synthesized proteins are rapidly degraded by the ubiquitin-proteasome system; however, the relationship of ubiquitination to translation for these proteins has been unclear. We report that cotranslational ubiquitination (CTU) is a robust process, with 12%–15% of nascent polypeptides being ubiquitinated in human cells. CTU products contained primarily K48-linked polyubiquitin chains, consistent with a proteasomal targeting function. While nascent chains have been shown previously to be ubiquitinated within stalled complexes (CTU^S), the majority of nascent chain ubiquitination occurred within active translation complexes (CTU^A). CTU^A was increased in response to agents that induce protein misfolding, while CTU^S was increased in response to agents that lead to translational errors or stalling. These results indicate that ubiquitination of nascent polypeptides occurs in two contexts and define CTU^A as a component of a quality control system that marks proteins for destruction while they are being synthesized.