[formula: see text] A library of fluoroaromatic inhibitors of carbonic anhydrase has been found to bind in a manner dependent on both hydrophobicity and the pattern of substitution of the fluoroaromatic ring. All of the compounds in the library bind to the protein with Kd < 3 nM. We have inferred two distinct binding modes from our data, which suggest two types of interactions that should be considered when designing fluorinated drugs.