Priming provides protection from dermonecrosis severity and MRSA burden in abscesses of BALB/c and C57BL/6 mice. Mice were preinfected (primed) with USA300 in the right flank, followed by resolution of infection over 6 weeks. Both naive and primed groups then received USA300 in both flanks, and the abscesses were monitored for 7 days. The mean dermonecrosis area (square millimeters) was measured at selected time points over 7 days postinfection. Visualization of skin abscesses on days 3, 5, and 7 in wild-type (WT) (A and C) and rag1−/− (B and D) mice showed smaller lesions in primed mice than in naive mice for both the BALB/c (A and B) and C57BL/6 (C and D) backgrounds. The dermonecrosis area was significantly reduced in primed mice compared to naive infected mice for both wild-type (E and I) and rag1−/− (G and K) mice. The number of MRSA CFU was significantly reduced in both wild-type (F and J) and rag1−/− (H and L) primed mice compared to naive mice. Left and right abscess areas were compared at day 5 postinfection (day of greatest abscess severity) for both wild-type (M) and rag1−/− (N) mice of both backgrounds. The lower limit of detection for bacterial densities was approximately 20 CFU/abscess. The statistical significance of differences was determined by comparison to naive infected mice (for wild-type mice, n ≥ 16; for rag1−/− mice, n ≥ 8), using Student's t test and one-way ANOVA (*, P < 0.05; **, P < 0.01; ***, P < 0.001). Data presented are means ± SD.