Nonsense-mediated decay (NMD) is a phylogenetically widely conserved mechanism that contributes to the fidelity of gene expression. NMD inhibits the accumulation of nonsense- or frameshift-mutated mRNA and thus minimizes the synthesis of truncated proteins with potential dominant negative effects. Yeast and higher eukaryotes use somewhat diverse mechanisms to promote NMD and to discriminate between premature and physiological translation termination codons. NMD in yeast involves the binding of specific RNA-binding proteins to cis-acting exonic elements. In contrast, NMD of the intron-containing genes of higher eukaryotes is splicing-dependent. Here, we investigated the NMD sensitivity of nonsense-mutated transcripts of the naturally intronless human melanocortin 4-receptor (MC4-R) gene. Nonsense-mutated variants of MC4-R transcripts are stable and express truncated proteins that are detectable in the lysates of transfected cells. Thus, the naturally intronless MC4-R gene and probably many other intronless genes fail to be monitored by the NMD pathway.