Objective: To report a case of peripheral and autonomic neuropathy following one cycle of bortezomib in a patient with newly diagnosed multiple myeloma. Case Summary: A 75-year-old male who was highly functional prior to therapy rapidly became bed-bound from hypotension, syncope, and peripheral neuropathy after initiating bortezomib. Orthostatic hypotension and syncope persisted despite exclusion of infection and endocrine derangements and his receiving adequate intravenous hydration. Five weeks after this single cycle, the patient had a complete treatment response, including undetectable M-spike, improved anemia, and return to baseline renal function. An objective causality assessment revealed that an adverse drug event was probable. Discussion: Although neurotoxicity is an adverse effect of bortezomib, a MEDLINE search revealed little evidence on autonomic neuropathy, such as orthostatic hypotension and syncope. Also unique is the patient's complete treatment response following this single cycle. One explanation for the toxicities and dramatic treatment response is increased bortezomib exposure due to decreased drug metabolism. Both drug interactions and genetic polymorphisms can reduce bortezomib metabolism via effects on cytochrome P450 enzymes. Our patient was concomitantly taking 4 CYP inhibitors; amiodarone and omeprazole were longstanding, and ciprofloxacin and fluconazole were recently initiated prior to chemotherapy. Of these, fluconazole inhibits CYP2C9, 2C19, and 3A4; amiodarone inhibits CYP3A4, 1A1, 1A2, 2B6, and 2D6; ciprofloxacin inhibits CYP1A2 and 3A4; and omeprazole inhibits CYP1A2, 2C19, 2C9, 2D6, and 3A4. Similarly, genetic variables affect CYP enzymes. Genetic testing can predict response to bortezomib therapy, but pretherapy testing is not standard practice due to availability and cost, as in our patient's case. Conclusions: CYP-inhibiting drugs and many genetic polymorphisms can reduce bortezomib metabolism and increase serum concentrations of the drug, but guidelines on drug-drug interactions, monitoring, and genetic testing prior to bortezomib toxicity are needed.