Acute interstitial nephritis is rarely reported with vancomycin. Literature searches revealed six biopsy-proven cases of vancomycin-induced interstitial nephritis. We report a case of a 51-year-old male who was treated with vancomycin and gentamicin for primary osteomyelitis with methicillin resistant Staphyloccocus aureus bacteremia. He developed rash and acute kidney injury after vancomycin therapy. Renal function continued to decline despite discontinuation of vancomycin and prednisone was initiated. Rapid improvement of kidney function was noted and the patient was discharged with an improved creatinine. There was a failure of compliance with steroid therapy, and a second episode of acute kidney injury developed. Creatinine again improved after restarting steroids. Physicians should consider interstitial nephritis when patients are on vancomycin even when they have been on the medication for weeks. Although there have been no controlled clinical trials on the efficacy of steroids in acute interstitial nephritis, it should still be considered if improvement is not evident after drug withdrawal.