Lateral line depigmentation (LLD) is a common condition in managed tropical saltwater fish, and treatment is somewhat elusive. Naltrexone, an opioid receptor antagonist, enhances epithelial cell replication, cytokine production, and angiogenesis to stimulate wound healing in mice. A treatment trial with 11 palette surgeonfish with LLD was performed. Seven fish underwent a single topical treatment of a mixture of 4 mg naltrexone and 10 g iLEX petroleum paste applied topically to LLD lesions. Four additional fish served as controls: two received only topical iLEX and two received no treatment. Severity of disease was scored on a 0-3 scale. Inflammatory response was gauged on a separate 0-3 scale for 5 d after treatment based on severity of erythema, as seen in a clinical case performed prior to this study. After 11 days, four affected animals that lacked an inflammatory response after naltrexone topical treatment were administered a single dose of intralesional 0.04% naltrexone (4 mg diluted into 10 ml saline). Lesions on all fish were photographed and measured at day 33. Clinical improvements in lesion size and pigmentation were apparent following topical naltrexone therapy in fish with severe lesions. Although these cases are promising, more data are needed to further evaluate the effectiveness of naltrexone 0.04% in treating LLD lesions in palette surgeonfish.