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Both positive selection and negative selection have been shown to drive the evolution of coding regions. It is of interest to know if the corresponding 5′ regions of genes may be subjected to selection of comparable intensities. For such a comparison, we chose the Accessory gland protein (Acp) genes as our test case. About 700 bp and 600 bp for the 5′ and coding regions, respectively, of eight previously unstudied genes were sequenced from 21 isogenic lines of D. melanogaster and one line from D. simulans. The ratio of divergence at the amino-acid replacement sites (A) over that at the synonymous sites (S) was twice the ratio for common polymorphism. Interestingly, the 5′ region shows the same trend, with the 5′/S divergence ratio being 1.8 times higher than the 5′/S ratio for common polymorphism. There are several possible explanations for the 5′/S ratios, including demography, negative selection, and positive selection. Under normal conditions, positive selection is the most likely explanation. If that is true, about 45 to 50 percent of all fixed differences at both the replacement and 5′ sites were adaptive, even though the substitution rate in the former is only half that of the latter (KA/KS ∼ 0.3 vs. K5′/KS ∼ 0.6). As previous analyses have indicated, the inclusion of slightly deleterious polymorphism confounds the inference of positive selection. The analysis of published polymorphism data covering 97 verified 5′ regions of Drosophila suggests more pronounced selective constraint on the 5′ untranslated region and the core promoter (together corresponding to ∼200 bp in this data set) when compared to the more distal portion of the 5′ region of genes.