(S)-2-Hydroxypropylphosphonate [(S)-2-HPP, 1] epoxidase (HppE) reduces H2O2 at its nonheme-iron cofactor to install the oxirane "warhead" of the antibiotic fosfomycin. The net replacement of the Cl pro-R hydrogen of 1 by its C2 oxygen, with inversion of configuration at Cl, yields the cis-epoxide of the drug [(1R,2S)-epoxypropylphosphonic acid (cis-Fos, 2)]. Here we show that HppE achieves similar to 95% selectivity for Cl inversion and cis-epoxide formation via steric guidance of a radical-coupling mechanism. Published structures of the HppE center dot Fe-II center dot 1 and HppE center dot Zn-II center dot 2 complexes reveal distinct pockets for C3 of the substrate and product and identify four hydrophobic residues-Leu120, Leu144, Phe182, and Leu193-close to C3 in one of the complexes. Replacement of Leu193 in the substrate C3 pocket with the bulkier Phe enhances stereoselectivity (cis:trans similar to 99:1), whereas the Leu120Phe substitution in the product C3 pocket diminishes it (similar to 82:18). Retention of Cl configuration and trans-epoxide formation become predominant with the bulk-reducing Phe182Ala substitution in the substrate C3 pocket (similar to 13:87), trifluorination of C3 (similar to 23:77), or both (similar to 1:99). The effect of C3 trifluorination is counteracted by the more constrained substrate C3 pockets in the Leu193Phe (similar to 56:44) and Leu144Phe/Leu193Phe (similar to 90:10) variants. The ability of HppE to epoxidize substrate analogues bearing halogens at C3, Cl, or both is inconsistent with a published hypothesis of polar cyclization via a Cl carbocation. Rather, specific enzyme substrate contacts drive inversion of the Cl radical-as proposed in a recent computational study-to direct formation of the more potently antibacterial cis-epoxide by radicaloid C-O coupling.