Purpose To test the hypothesis that the C-X-C chemokines CXCL1, CXCL2, and CXCL10 contribute to inflammation during Staphylococcus aureus endophthalmitis. Methods S. aureus endophthalmitis was induced by intravitreal injection of 5000 colony forming units of S. aureus into the eyes of C57BL/6J, CXCL1 −/− , CXCL2 −/− , or CXCL10 −/− mice. At 12, 24, and 36 hours postinfection, bacterial counts, intraocular inflammation, and retinal function were assessed. Based on these results, the effectiveness of intravitreal administration of anti-CXCL1 in reducing inflammation and improving retinal function was evaluated in S. aureus– infected C57BL/6J mice. Results We observed significant attenuation of inflammation and improvement in retinal function in CXCL1 −/− mice relative to C57BL/6J at 12 hours but not at 24 or 36 hours postinfection with S. aureus . Co-administration of anti-CXCL1 antibodies with S. aureus , however, did not improve retinal function or reduce inflammation at 12 hours postinfection. In CXCL2 −/− and CXCL10 −/− mice, retinal function and intraocular inflammation were not significantly different from those of C57BL/6J mice at 12 and 24 hours postinfection. At 12, 24, or 36 hours, an absence of CXCL1, CXCL2, or CXCL10 did not alter intraocular S. aureus concentrations. Conclusions CXCL1 appears to contribute to the early host innate response to S. aureus endophthalmitis, but treatment with anti-CXCL1 did not effectively limit inflammation in this infection. CXCL2 and CXCL10 did not seem to play an integral role in inflammation during the early stages of S. aureus endophthalmitis.