Intravenous lidocaine is increasingly being utilized as an opioid-sparing analgesic. A 55-year-old man with well-controlled human immunodeficiency virus on highly active antiretroviral therapy was prescribed a lidocaine infusion at 1 mg/kg/h for postoperative pain. On postoperative day 2, the patient experienced 4 unresponsive episodes with tachycardia, hypertension, and oxygen desaturation. Serum lidocaine level was available 2 days later (high 6.3 µg/mL, therapeutic range 2.5–3.5 µg/mL). There is significant pharmacokinetic interaction between lidocaine and this patient’s human immunodeficiency virus medications. This case highlights the need for a readily accessible list of medications that caution against lidocaine. We propose in-house serum lidocaine levels to monitor patients at an increased risk for toxicity.