Reportedly, more people in Japan are prescribed benzodiazepine (BZD) than elsewhere. The amount of propofol required for the intravenous sedation of patients receiving long-term BZD might be affected by drug interactions, competitive enzyme inhibition, enzyme induction, and a central change in sensitivity. However, the details about such drug interactions are unclear. The total administered doses during intravenous sedation with propofol alone and local anesthesia for the extraction of impacted mandibular wisdom teeth on both sides were retrospectively compared for a four-year period (from 2009 to 2012) between patients who had been using oral BZD for at least six months (BZD, n = 24) and those who did not (Control, n = 307). A significandy lower dose of propofol was required for intravenous sedation in the BZD group than in the control group (4.83± 1.30 vs5.91 ± 1.25 mg/kg/h, p = 0.0005;95% confidence interval [CI] of effect size, -1.22 to -0.94; Cohen's d, 0.84). This result was not influenced by whether oral BZD was taken on the day of surgery. Long-term oral BZD use was significantly associated with a lower propofol dose after corrections for patient age. The present results and the mechanisms of drug interaction suggest that the smaller propofol requirement for intravenous sedation in patients with long-term oral BZD use was not due to an additive effect, the down-regulation of the central nervous system, or enzyme induction. Instead, the smaller propofol requirement might be due to competitive enzyme inhibition via the enzyme involved in glucuronate conjugation or competitive albumin binding. In summary, clinicians should be aware that patients with long-term oral BZD use might require a lower dose of propofol than those without BZD use regardless of whether BZD was taken on the day of surgery.