The metabolite profiles, kinetics and susceptibility to inactivation of four allelic variants of CYP2D6 were analyzed in the current study. The variants included three variants of CYP2D6 with a series of distal mutations (*34, *17-2, *17-3) and one ultra-metabolizer (*53), and one active-site mutant (CYP2D6-T309AT). The prototypical substrates bufuralol and dextromethorphan were used in analyses as well as the known mechanism-based inactivator SCH66712. Decreased enzyme efficiencies for metabolism of dextromethorphan and bufuralol were observed for *34, *17-2, and *17-3 while *53 showed increased activity consistent with its designation as an ultra-metabolizer. The active site mutant CYP2D6-T309A displayed similar kinetic values as reference CYP2D6*1. Both *53 and CYP2D6-T309A showed altered metabolite profiles as compared to *1, particularly with dextromethorphan as substrate. These findings support the roles of Phe120 (changed to Ile in *53) and Thr309 in determining product regio-selectivity. Likewise, though *1 was inactivated by SCH66712, *53 and T309A were less susceptible to inactivation. These findings support the designation of T309A as the nucleophilic target for inactivation of CYP2D6 by SCH66712 and suggest Phe120 may also play a role in inactivation. The inactivation of *1 and *53 by SCH66712 was further investigated through determination of the partition ratio. Comparison of the partition ratio values showed *53 with partition ratio of ~25 turns over more product before being inactivated than *1 with partition ratio of ~3. The decreased rate of inactivation of *53 suggests that inactivation may be dependent on time within and positioning of inactivator in the active site. Furthermore, the reduction in inactivation of *53 and CYP2D6-T309A may be due to altered product regio-selectivity. Cumene hydroperoxide was used as an oxygen surrogate to determine the role of oxygen activation in altered product formation and inactivation with *53 and CYP2D6-T309A. (Support: NIH [LLF] 1R15-GM086767-02,-03; by the Cook, Heyl, Hutchcroft, and Varney funds of Kalamazoo College, and by a grant to Kalamazoo College from the HHMI ).