E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a–d, the corresponding halohydrins 6 a–d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin (R,S)‐6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through “substrate‐based” stereocontrol. The RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % diastereomeric excess (de) and (S,S)‐6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an “inverted” mode in comparison to tert‐butyloxycarbonyl‐ and methyloxycarbonyl‐protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % de and (S,S)‐6 b with 95 % conversion and 86 % de. Choose your side, not your enzyme: A single alcohol dehydrogenase is able to reduce structurally related chloroketones derived from S‐amino acids with the opposite enantiopreference to furnish both (R,S) and (S,S)‐chlorohydrins. Stereocontrol is achieved by changing the N‐protecting group in the substrate, which allows the preparation of stereocomplementary halohydrins using the same biocatalyst.