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Pregabalin is gaining popularity in the perioperative period for its usefulness in treating neuropathic pain and its apparent opioid- sparing effect. The present report describes the perioperative course of three patients who received pregabalin and experienced significant respiratory depression in the postoperative period. All three patients consented to the report and publication of the present case series. The first patient was elderly with borderline renal dysfunction. She experienced respiratory arrest in the immediate postoperative period following a craniotomy for tumour excision. The second patient presented with severe respiratory depression 12 h after receiving a spinal anesthetic for joint replacement, and was later found to have clinically significant obstructive sleep apnea. The third patient, who was an otherwise healthy elderly individual on benzodiazepines for anxiety, experienced respiratory arrest in the postanesthesia care unit after an uneventful anesthesia for lumbar spine decompression. All of these patients were treated successfully with standard resuscitation measures. Although other causes of respiratory depression in these patients were considered, there appears to be an association between pregabalin and this complication. The present article briefly reviews the evidence regarding the perioperative use of pregabalin. Based on the authors' experience and the available evidence, they believe that pregabalin may be useful in the management of acute pain in carefully selected patients undergoing certain surgeries. A clinical algorithm has been developed to guide the perioperative use of pregabalin. This algorithm may be helpful in increasing the safety of perioperative pregabalin use.