In rats receiving a low oral dose (0.35 mg/kg p.o.) of trifluoperazine (TFP), a potent neuroleptic phenothiazine, the parent drug distribution was separate from that of its metabolite trifluoperazine sulfoxide (TFP-SO). This was not seen after intraperitoneal administration (i.p.) of the same or high dose (5mg/kg). TFP-SO was not detected in the brain, wheras TFP was significantly associated with microsomes when its brain level was highest. Absorption, distribution, metabolism, and dose dependent excretion procedded rapidly with 97% of a dose recovered 24 hr after p.o. treatment, only 6% in the urine and the remainder in feces with 87% of this metabolized to compounds other than TFP-SO. TFP and its metabolites arrived in feces via two pathways, largely the bile plus another route. The excretion pattern was unchanges with other drugs or after treatment for 3 wk, although excretion differed on the first day after i.p. and p.o. administration.