In-depth kinetic and mechanistic studies on the reversible binding of NO to water-soluble iron(III) porphyrins as a function of pH revealed unexpected reaction kinetics for monohydroxo-ligated (P)Fe-III(OH) species formed by deprotonation of coordinated water in diaqua-ligated (P)Fe-III(H2O)(2). The observed significant decrease in the rate of NO binding to (P)Fe(OH) as compared to that of (P)Fe(H2O)(2) does not conform with expectations based on previous mechanistic work on NO-heme interactions, which would point to a diffusion-limited reaction for the five-coordinate Fe-III center in (P)Fe(OH). The decrease in rate and an associatively activated mode of NO binding observed at high pH is ascribed to an increase in the activation barrier related to spin state and structural changes accompanying NO coordination to the high-spin (P)Fe-III(OH) complex. The existence of such a barrier has previously been observed in the reactions of five-coordinate iron(II) hemes with CO and is evidenced for the first time for the process involving coordination of NO to the iron heme complex. The observed reactivity pattern, relevant in the context of studies on NO interactions with synthetic and biologically important hemes (in particular, hemoproteins), is reported here for an example of a simple water-soluble iron(III) porphyrin [meso-tetrakis(sulfonatomesityl)-porphinato]-iron(III), (TMPS)Fe-III.