The aim of this study was to investigate in-hospital mortality and 12-month mortality in patients with coagulase-negative Staphylococcus (CoNS) compared to Staphylococcus aureus (S. aureus) infective endocarditis (IE). We used a prospective cohort study of 66 consecutive CoNS and 170 S. aureus IE patients, collected at 2 tertiary university hospitals in Copenhagen (Denmark) and at 1 tertiary university hospital in Gothenburg (Sweden). Median (range) C-reactive protein at admission was higher in patients with S. aureus IE (150 mg/l (1521) vs 94 mg/l (6303); p<0.001), which may suggest a more serous infection. CoNS was associated with prosthetic valve IE (49% vs 24%; p<0.001) and median diagnostic delay was longer in CoNS IE patients (20 d (0232) vs 9 d (0132); p<0.001). In-hospital mortality was equally high in both groups but 25% of the CoNS IE patients had died after 1 y compared to 39% of patients with S. aureus IE (p =0.05). In conclusion, CoNS IE was associated with a long diagnostic delay and high in-hospital mortality, whereas post-discharge prognosis was better in this group of patients compared to patients with IE due to S. aureus.