The authors evaluated the efficacy and safety of an OPAT program in a small group of patients affected by infective endocarditis. Three patients were considered eligible for the treatment; i.e. they had a stable hemodynamic balance and no embolic events. Streptococcus spp. grew in blood cultures of two patients, while blood cultures were negative in the third patient. Long-acting antibiotics were used and all patients recovered from the infection without adverse events. The treatment was efficacious and safe. This preliminary experience suggests that OPAT programs can be promoted in infective endocarditis with advantage. Strictness and caution are necessary in screening and monitoring patients.