Several sulfonamides used as antibacterial or diuretic drugs are potent alkaline phosphatase inhibitors. The mechanism of inhibition may involve binding of the zinc in the active site of the enzyme by the unbonded electron pair on the sulfonamide group nitrogen atom as well as binding of the drug to a second site. Addition of progressively larger groups to this nitrogen leads to an increasing loss of inhibitory capability. Isoenzymes from human liver, bone, kidney, granulation tissue and intestine are inhibited to a similar extent while the placenta isoenzyme is more resistant. It is suggested that some pharmacologic actions of sulfonamides may be due to inhibition of alkaline phosphatase, rather than carbonic anhydrase.