Objective. Primary lateral sclerosis (PLS) is a rare idiopathic neurodegenerative disorder affecting upper motor neurons and characterized by spasticity, muscle weakness, and bulbar involvement. It can sometimes mimic early stage of more common and fatal amyotrophic lateral sclerosis (ALS). Surgical patients with a history of neurodegenerative disorders, including PLS, may be at increased risk for general anesthesia related ventilatory depression and postoperative respiratory complications, abnormal response to muscle relaxants, and sensitivity to opioids, sedatives, and local anesthetics. We present a case of a patient with PLS and recent diagnosis of breast cancer who underwent a simple mastectomy surgery uneventfully under an ultrasound guided thoracic paravertebral block, multimodal analgesia, and monitored anesthesia care. Patient reported minimal to no pain or discomfort in the postoperative period and received no opioids for pain management before being discharged home. In patients with PLS, thoracic paravertebral block and multimodal analgesia can provide reliable anesthesia and effective analgesia for breast surgery with avoidance of potential risks associated with general anesthesia, muscle paralysis, and opioid use.