To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved. The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extended-release tablet with 250 mL commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit or water in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) was determined. Furanocoumarin and naringenin precursor (naringin) concentrations were measured in each grapefruit treatment. Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than that with water. Felodipine peak concentration was higher, but the half-life was unchanged. The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumarins produced mechanism-based and competitive inhibition of CYP3A4. Bergamottin was the most potent mechanism-based inhibitor. Naringenin isomers produced only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, and naringin concentrations varied among grapefruit treatments but were sufficient to inhibit markedly in vitro CYP3A4 activity. Unprocessed grapefruit can cause a drug interaction with felodipine. The active ingredients are naturally occurring in the grapefruit. Bergamottin is likely important in drug interactions with commercial grapefruit juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.