Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) greatly complicates treatment of skin and soft tissue infections (SSTI). It was previously found that subcutaneous (SQ) treatment with the mononuclear phagocyte (MP)-selective activator, complement peptide-derived immunostimulant-02 (CPDI-02; formerly EP67), increases prophylaxis of outbred CD-1 mice against SQ infection with CA-MRSA. Here, we determined if treatment with CPDI-02 also increases curative protection. Methods: Female CD-1 mice were challenged SQ with CA-MRSA USA300 LAC then CPDI-02 or inactive scCPDI-02 was administered by a topical, SQ, IM, or IV route at 6- or 24-hrs post-challenge. Dermal abscess sizes were compared over 10 days and CA-MRSA burden, neutrophils, MP, and pro-inflammatory cytokines were compared in dermal abscesses. CPDI-02 PK and distribution in female CD-1 mice were compared after IM or IV dosing and CPDI-02 toxicity in male and female CD-1 mice was determined by IM dose escalation and repeat IM dosing. Results: Repeat IM treatment starting at 6-hrs post-challenge decreased maximum abscess surface area, CA-MRSA burden, and time to resolution, whereas repeat treatment by a topical, SQ, or IV route had no effect. Repeat treatment starting at 24-hrs post-challenge was ineffective by the current routes. Single IM treatment starting at 6-hrs post-challenge was as effective as repeat IM treatment, increased systemic exposure to CPDI-02, and, in dermal abscesses, initially decreased IL-1β and increased MP. CPDI-02 was tolerated to between 130-170 mg/kg after IM dose escalation and between 65-130 mg/kg after repeat IM dosing with males being more tolerant. Conclusions: Single early-stage IM treatment with CPDI-02 may increase curative protection against SSTI caused by CA-MRSA and/or other pathogens controlled by activated MP.