To better understand the role of alternative splicing, we conducted a large-scale analysis of reliable alternative isoforms of known human genes. Each isoform was classified according to its splice pattern and supporting evidence. We found that one-third of the alternative transcripts examined contain premature termination codons, and most persist even after rigorous filtering by multiple methods. These transcripts are apparent targets of nonsense-mediated mRNA decay (NMD), a surveillance mechanism that selectively degrades nonsense mRNAs. Several of these transcripts are from genes for which alternative splicing is known to regulate protein expression by generating alternate isoforms that are differentially subjected to NMD. We propose that regulated unproductive splicing and translation (RUST), through the coupling of alternative splicing and NMD, may be a pervasive, underappreciated means of regulating protein expression.