The aim of this study was to describe the immediate and long-term prognosis of a contemporary cohort of patients with left-sided infective endocarditis (LSIE). A prospective observational cohort study was conducted in a referral centre. Between January 2000 and December 2011, all consecutive adult patients with LSIE were followed-up until death, relapse, recurrence, need for late surgery, or last control. During the active phase of IE, 174 of 438 patients underwent surgery (40% overall; 43% native valve (NVIE), 30% prosthetic valve (PVIE)) and 125 died (29% overall; 26% NVIE, 39% PVIE). The median follow-up in survivors was 3.2years (interquartile range (IQR) 1.0-6.0years). Relapses occurred in seven patients (2.2%; 95% CI, 1.1-4.5) and recurrences in eight (2.6%; 95% CI, 1.3-5.0), with an incidence density of 0.0067 per patient-year (95% CI, 0.0029-0.0133) and high mortality (75% of recurrences). Only four of 130 survivors (3.1%; 95% CI, 1.2-7.6) who were treated surgically during the active phase of the disease, and 14/183 (7.7%; 95% CI, 4.6-12.4) of those not undergoing surgery needed operation during follow-up (p 0.09). In the 313 survivors, actuarial survival was 86% at 1year (87% NVIE, 83% PVIE), 79% at 2years (81% NVIE, 72% PVIE) and 68% at 5years (71% NVIE, 57% PVIE). At 1year, 115 of 397 patients (29.0%; 95% CI, 24.7-33.6) remained alive, with no surgery requirement, relapse or recurrence. LSIE is associated with considerable in-hospital and long-term mortality, especially PVIE. However, relapses, recurrences and the need for late surgery are uncommon. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.