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The expression of heterologous proteins in E. coli is strongly affected by trongly aaffected codon bias. This phenomenon occurs when the codon usage of the mRNA coding for the foreign protein differs from that of E. coli resulting in frequent ribosome pausing. To overcome this effect, E. coli strains engineered to provide high levels of rare tRNAs are available (CodonPlus, CP). However, the increased speed of translation could cause aggregation of slow folding domains. To test this possibility, we have studied the expression of eight proteins from plants in E. coli BL21(DE3)pLysS´ and CP. First, we sorted them in two groups according to the percentage of rare codon content (RCC) (group L, RCC<5%; group H, RCC>5%). We then assessed the solubility of the proteins and found that the group L proteins were highly soluble in both strains. However, the group H proteins were localized in the insoluble fraction when expressed in the CP strain, while a portion could be recovered in the soluble fraction when expressed in the pLysS´ strain. Moreover, the expression of group H proteins in the CP strain caused retarded growth and low cell yield due to massive accumulation of inclusion bodies. Our results show that the expression of high RCC proteins in the CP strain is detrimental for protein solubility. We propose that the RCC could be a useful predictor of protein solubility in codon bias-adjusted strains.