Nearly half of all states have legalized medical marijuana or recreational-use marijuana. As more states move toward legalization, the effects on injured patients must be evaluated. This study sought to determine effects of cannabis positivity at the time of severe injury on hospital outcomes compared with individuals negative for illicit substances and those who were users of other illicit substances. A Level I trauma center performed a retrospective chart review covering subjects over a 2-year period with toxicology performed and an Injury Severity Score (ISS) of more than 16. These individuals were divided into the negative and positive toxicology groups, further divided into the marijuana-only, other drugs-only, and mixed-use groups. Differences in presenting characteristics, hospital length of stay, intensive care unit (ICU) stays, ventilator days, and death were compared. A total of 8,441 subjects presented during the study period; 2,134 (25%) of these had toxicology performed; 843 (40%) had an ISS of more than 16, with 347 having negative tests (NEG); 70 (8.3%) substance users tested positive only for marijuana (MO), 323 (38.3%) for other drugs-only, excluding marijuana (OD), and 103 (12.2%) subjects showed positivity for mixed-use (MU). The ISS was similar for all groups. No differences were identified in Glasgow Coma Scale (GCS), ventilator days, blood administration, or ICU/hospital length of stay when comparing the MO group with the NEG group. Significant differences occurred between the OD group and the NEG/MO/MU groups for GCS, ICU length of stay, and hospital charges. Cannabis users suffering from severe injury demonstrated no detrimental outcomes in this study compared with nondrug users.