Isocitrate dehydrogenase (IDH) 1/2 gain-of-function variants catalyze the production of the oncometabolite 2-hydroxyglutarate and are validated targets for leukemia treatment. We report binding and inhibition studies on 13 IDH1/2 variant inhibitors, including clinical candidates and drugs, with wild-type (wt) IDH1 and its cancer-associated variant, IDH1 R132H. Interestingly, all the variant inhibitors bind wt IDH1 despite not, or only weakly, inhibiting it. Selective inhibition of the IDH1 R132H variant over wt IDH1 does not principally relate to the affinities of the inhibitors for the resting forms of the enzymes. Rather, the independent binding of Mg2+ and 2-oxoglutarate to the IDH1 variant makes the variant more susceptible to allosteric inhibition, compared to the tighter binding of the isocitrate-Mg2+ complex substrate to wt IDH1. The results highlight that binding affinity need not correlate with inhibition selectivity and have implications for interpretation of inhibitor screening results with IDH and related enzymes using turnover versus binding assays.