Enrofloxacin is a fluoroquinolone widely used in animals including fish. Intramuscular (IM) injection of enrofloxacin is a feasible and efficacious option for drug delivery. In many species IM injection has been associated with injection site reactions and increases in serum muscle enzymes. Injection site reactions have not been well characterized in fish. Three groups of striped bass (Morone saxatilis) received an IM injection of enrofloxacin 2.27% in the right epaxial musculature 24, 48, or 96 hr prior to evaluation. Mean dose was 7.69 mg/ kg (6.14–9.69 mg/kg). The 24- and 48-hr groups received an injection of equal-volume 0.9% saline in the left epaxial musculature. A corresponding noninjected tissue sample was designated in the left epaxial musculature from each fish of the 96-hr group. Fish were euthanized and injection sites and noninjection control sites were evaluated grossly and histologically. Grades 1–4 were assigned to samples, with grade 1 corresponding to normal tissue and grades 2, 3, and 4 corresponding to mild, moderate, and severe inflammation and/or necrosis respectively. Externally, all control and injection sites appeared visually unremarkable. On cut surface, epaxial muscle of the enrofloxacin-injected tissue appeared moderately to severely hemorrhagic compared to saline and noninjected tissue, which was normal or mildly hemorrhagic. Histologically, eight of eight noninjected tissues were grade 1. For saline-injected tissues, 14 of 16 tissues were grade 2 and 2 samples were grade 3 when 24- and 48-hr groups were combined. For enrofloxacin-injected tissues, 8 of the 8 24-hr samples were grade 3 and 16 of the 16 48- and 96-hr samples were grade 4. These data show that IM injection of enrofloxacin 2.27% is associated with severe hemorrhage, necrosis, and inflammation in striped bass, and may negatively affect animal welfare.