Posttranscriptional processes often involve specific signals in mRNAs. Because mRNAs of integral membrane proteins across evolution are usually translated at distinct locations, we searched for universally conserved specific features in this group of mRNAs. Our analysis revealed that codons of very hydrophobic amino acids, highly represented in integral membrane proteins, are composed of 50% uracils (U). As expected from such a strong U bias, the calculated U profiles of mRNAs closely resemble the hydrophobicity profiles of their encoded proteins and may designate genes encoding integral membrane proteins, even in the absence of information on ORFs. We also show that, unexpectedly, the U-richness phenomenon is not merely a consequence of the codon composition of very hydrophobic amino acids, because counterintuitively, the relatively hydrophilic serine and tyrosine, also encoded by U-rich codons, are overrepresented in integral membrane proteins. Interestingly, although the U-richness phenomenon is conserved, there is an evolutionary trend that minimizes usage of U-rich codons. Taken together, the results suggest that U-richness is an evolutionarily ancient feature of mRNAs encoding integral membrane proteins, which might serve as a physiologically relevant distinctive signature to this group of mRNAs.