OBJECTIVES: The objectives were (1) to conduct cluster analysis to explore patterns of outpatient prescription medications during the first year after combat-related amputations and (2) to analyze patient characteristics associated with prescription medication clusters. DESIGN: Retrospective study of Department of Defense casualty records and outpatient prescription medications during the first year postinjury. Hierarchical cluster analysis of American Hospital Formulary Service (AHFS) medication classes. SETTING: Military amputation rehabilitation program. PARTICIPANTS: A total of 1651 US service members who sustained major limb amputations in Operations Iraqi and Enduring Freedom from 2001 to 2017 and had outpatient prescription medications. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Prescription medication clusters and patient characteristics. RESULTS: Cluster analysis identified 3 prescription medication profiles. Cluster 1: baseline (n=682) consisted of 6 AHFS classes: cathartics/laxatives, anticonvulsants, semisynthetic opioids, antidepressants, nonsteroidal anti-inflammatory drugs, and combination opioid analgesics. These 6 classes were part of all 3 profiles (ie, baseline medications). Cluster 2: baseline plus insomnia (B+I) (n=502): atypical antipsychotics, anxiolytics/sedatives, methadone, benzodiazepines, analgesics/antipyretics, and baseline medications. Cluster 3: baseline plus severe injury (B+SI) (n=467): anticoagulants, 5-HT3 receptor antagonists, multivitamins, anxiolytics/sedatives, analgesics/antipyretics, and baseline medications. The baseline cluster was characterized by early injury years (85%, 2001-2008), moderate/serious injuries (85%), single amputation, chronic pain, and posttraumatic stress disorder. Cluster B+I was characterized by early injury years (62%), minor injuries (16%), low rates of traumatic amputations, and postinjury complications. Cluster B+SI was characterized by later injury years (88%, 2009-2017), serious/severe injuries (62%), multiple amputations (42%), traumatic brain injury (43%), high rates of complications, and prescriptions. CONCLUSIONS: Cluster analysis identified 3 outpatient prescription medication profiles during the first year postinjury. All profiles included analgesics and psychotherapeutics but differed in specific insomnia medications, multivitamins, and anticoagulants. Medication profiles had significant associations with injury years, injury severity, and postinjury complications. The results inform future research and prescription medication practices.