We retrospectively collected plasma level assessments performed in 96 adult patients with epilepsy on stable monotherapy, including 9 patients on clobazam (CLB), 34 on carbamazepine (CBZ), 24 on phenobarbital (PB), 9 on phenytoin (PHT), and 20 on valproate (VPA); these results were compared to those obtained in 54 adult patients on stable bitherapy with the association of CLB with either CBZ (n = 17), PB (n = 17), PHT (n = 5), or VPA (n = 15). Our results show that CLB has no significant effect on the level to dose ratio (LDR) of CBZ, PB, PHT, or VPA. Conversely, CBZ, PB, and PHT significantly decrease the LDR of CLB. CBZ and PHT significantly increase the LDR of N-desmethylclobazam (NCLB), the major metabolite of CLB. A significant increase in the NCLB/CLB ratio was found in CBZ + CLB, PB + CLB, and PHT + CLB bitherapies. These findings are of clinical significance: clobazam is useful as adjunctive treatment in human epilepsy and is often chosen as the benzodiazepine adjunctive drug in chronic resistant epilepsy. Sedative side effects may occur, especially in patients treated by a CBZ + CLB or PHT + CLB bitherapy, and both CLB and NCLB plasma levels should be monitored in such patients.