Given the structure of the genetic code, synonymous codons differ in their capacity to minimize the effects of errors due to mutation or mistranslation. I suggest that this may lead, in protein-coding genes, to a preference for codons that minimize the impact of errors at the protein level. I develop a theoretical measure of error minimization for each codon, based on amino acid similarity. This measure is used to calculate the degree of error minimization for 82 genes of Drosophila melanogaster and 432 rodent genes and to study its relationship with CG content, the degree of codon usage bias, and the rate of nucleotide substitution. I show that (i) Drosophila and rodent genes tend to prefer codons that minimize errors; (ii) this cannot be merely the effect of mutation bias; (iii) the degree of error minimization is correlated with the degree of codon usage bias; (iv) the amino acids that contribute more to codon usage bias are the ones for which synonymous codons differ more in the capacity to minimize errors; and (v) the degree of error minimization is correlated with the rate of nonsynonymous substitution. These results suggest that natural selection for error minimization at the protein level plays a role in the evolution of coding sequences in Drosophila and rodents.