The second of three short upstream open reading frames (uORF2) in the transcript leader of the human cytomegalovirus gp48 (gpUL4) virion glycoprotein gene inhibits downstream translation approximately 10-fold. Remarkably, this inhibition depends on the amino acid coding information of uORF2. In the current studies we demonstrate that expression of the cistron downstream from uORF2 depends on ribosomes bypassing the uORF2 AUG codon (AUG2) by a leaky scanning mechanism. Replacing the nucleotides surrounding the wild-type AUG2 codon with those optimal for translation initiation reduces downstream translation approximately 10-fold. Analyses of mutants in which uORF2 either overlaps or is in frame with the downstream reading frame reveal that the initiation frequency at the wild-type AUG2 codon is surprisingly low; rather, the majority of ribosomal subunits bypass the wild-type AUG2 codon because of its suboptimal context. We propose a model to explain this unprecedented example of a paradoxically strong inhibitory effect of an upstream ORF despite inefficient utilization of its initiation codon.