Rifampin is a commonly used antimicrobial that is also a strong inducer of several drugmetabolizing enzymes. It is well documented to cause a large number of clinically significant drug interactions. Oxycodone, a semisynthetic opioid receptor agonist, is widely used for the management of postoperative pain and metabolized by the cytochrome P450 system. However, clinical studies regarding the rifampin-oxycodone interaction is limited. There are only few case reports about it in the English literature so far. We present a case of a 51-year-old male who was treated with rifampin and concomitant oxycodone and suffered from intractable postoperative pain to illustrate a contemporary understanding of rifampin drug interaction with oxycodone.