Nocardia infection classically occurs in immuno-compromized patients. Only a few cases of mediastinal infection due to this pathogen have been described in the literature. We report a patient who developed mediastinitis due to Nocardia asteroides after cardiac transplantation. The treatment was surgical debridement, dressing, sugaring and antibiotic therapy. The emergence of a severe acute renal failure possibly induced by drug interaction between Cyclosporin, cyclines and aminoglycosides, led us to modify the antimicrobial treatment. The intravenous use of Imipenem 2 g per day and Ciprofloxacin 400 mg per day for four weeks and then oral Ciprofloxacin 1.5 g per day for 1 year, was effective and allowed a good outcome, without any drug interaction with Cyclosporin, adverse effect, graft rejection episode or infection relapse.