An approximately 6.9-kb region encompassing the RpII215 gene was sequenced for 24 individuals of the island endemic species Drosophila guanche. The comparative analysis of synonymous polymorphism and divergence in D. guanche and D. subobscura, two species with pronounced differences in population size, allows contrasting the nearly neutral character of synonymous mutations. In D. guanche, unlike in D. subobscura, (1) the ratio of preferred to unpreferred synonymous changes was similar for polymorphic and fixed changes, (2) the numbers of preferred and unpreferred changes, both polymorphic and fixed, could be explained by the mutational process, and (3) the estimated scaled selection coefficient for unpreferred mutations did not differ significantly from zero. Additionally, the comparative analysis revealed that both the ratio of preferred to unpreferred synonymous changes and the frequency spectrum of unpreferred polymorphic mutations differed significantly between species. All these results indicate that a large fraction of synonymous mutations in the RpII215 gene behave as effectively neutral in D. guanche, whereas they are weakly selected in D. subobscura. The reduced efficacy of selection in the insular species constitutes strong evidence of the nearly neutral character of synonymous mutations and, therefore, of the role of weak selection in maintaining codon bias.