Aripiprazole, a relatively new antipsychotic drug, is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP2D6 to an active metabolite, dehydroaripiprazole. As studies on pharmacokinetic drug interactions with aripiprazole are so far limited, the aim of the present study was to investigate the impact of comedication on serum concentrations of aripiprazole and dehydroaripiprazole in psychiatric patients in a clinical setting. A therapeutic drug monitoring database was screened for patients receiving aripiprazole tablets as part of their treatment. Of the 361 samples included, 78% were from patients receiving comedication. The remaining 79 samples constituted the control group. Steady-state dose-adjusted serum concentrations (concentration to dose ratios, C:D ratios) of aripiprazole, dehydroaripiprazole and the sum of aripiprazole and dehydroaripiprazole, and the metabolic ratio (dehydroaripiprazole/aripiprazole) in the different comedication groups were compared with controls. Coadministration of a CYP3A4 inducer resulted in approximately 60% lower mean C:D ratios of aripiprazole, dehydroaripiprazole, and the sum of aripiprazole and dehydroaripiprazole (P < 0.05, P < 0.01, and P < 0.01, respectively). Combination with a CYP2D6 inhibitor resulted in a 45% higher mean C:D ratio of aripiprazole (P < 0.05), with no effect on the C:D ratio of dehydroaripiprazole. When aripiprazole was coadministered with alimemazine or lithium, a 56% (P < 0.01) and 43% (P = 0.05) higher mean C:D ratio of aripiprazole, respectively, was observed. Olanzapine, risperidone injections, escitalopram, or lamotrigine also had statistically significant effects on aripiprazole disposition but to a lesser extent. In conclusion, concurrent treatment with CYP3A4 inducers, CYP2D6 inhibitors, alimemazine, or lithium resulted in changes in the systemic exposure of aripiprazole between 40% and 60%. This is of such a magnitude that dose adjustments of aripiprazole may be required.