<b><i>Background/Aims:</i></b> The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction. <b><i>Methods:</i></b> This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest. <b><i>Results:</i></b> Bupropion plus nebivolol increased the mean peak plasma concentrations (C_max) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant. <b><i>Conclusion:</i></b> The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation.