Depending on the strain of immunodeficient mice, Corynebacterium bovis infection can be asymptomatic or cause transient or prolonged skin disease. C. bovis infection of NOD. Cg- Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice results in clinical skin disease that progresses in severity. Amoxicillin metaphylaxic and prophylaxic therapy prevents transmission and infection of mice after exposure to C. bovis and inhibits the growth of C. bovis isolates at therapeutic doses that are clinically achievable in mice. Amoxicillin is not efficacious for treatment of transient clinical skin disease in athymic nude mice, but the efficacy of amoxicillin treatment has not previously been characterized in C. bovis -infected NSG mice. In the current study, NSG mice were treated with amoxicillin beginning at 5 wk after exposure to C. bovis, at which time they had well-established clinical signs of disease. Clinical signs were scored to assess disease progression, regression, and reappearance. Our results showed that amoxicillin treatment for 3 or 6 wk reduced the clinical scores of NSG mice with C. bovis -associated clinical disease. In addition, withdrawal of treatment led to the recurrence of clinical signs. Collectively, our data suggest that amoxicillin treatment is effective in alleviating the clinical signs associated with C. bovis infection for the duration of treatment in NSG mice. Clinical intervention with antibiotics for C. bovis -infected NSG mice can be an option for management of C. bovis -related clinical disease either before or during facility-wide remediation efforts.