Fluvoxamine is a new antidepressant and selectively inhibits serotonin reuptake (SSRI). The present study demonstrates that fluvoxamine is a very potent inhibitor of the high-affinity O-deethylation of phenacetin, which is catalysed by cytochrome P4501A2 (CYP1A2), in microsomes from three human livers. Thus, the apparent inhibitor constant of fluvoxamine, Ki, ranged from 0.12 to 0.24 μM. Seven other SSRIs, citalopram, N-desmethylcitalopram, fluoxetine, norfluoxetine, paroxetine, sertraline and litoxetin either did not inhibit or were weak inhibitors of the O-deethylation of phenacetin. Our findings explain the mechanism of the pharmacokinetic interactions between fluvoxamine and drugs that are metabolized by CYP1A2, e.g. theophylline and imipramine.