Infective endocarditis (IE) caused by Staphylococcus species (spp.) is believed to be associated with higher morbidity and mortality rates. We hypothesize that Staphylococcus spp. are more virulent compared with other commonly causative bacteria of IE with regard to short-term and long-term mortality. It remains unclear if patients suffering from IE due to Staphylococcus spp. should be referred for surgical treatment earlier than other IE patients to avoid septic embolism and to optimize perioperative outcomes. The database of the CAMPAIGN registry, comprising 4917 consecutive patients undergoing heart valve surgery, was retrospectively analyzed. Patients were divided into 2 groups with regard to the identified microorganisms: Staphylococcus group and the non- Staphylococcus group. The non- Staphylococcus group was subdivided for further analyses: Streptococcus group, Enterococcus group, and all other bacteria groups. The respective mortality rates at 30 days (18.7% vs 11.8%; P <0.001), 1 year (24.7% vs 17.7%; P <0.001), and 5 years (32.2% vs 24.5%; P <0.001) were significantly higher in Staphylococcus patients (n=1260) compared with the non- Staphylococcus group (n=1787). Multivariate regression identified left ventricular ejection fraction <30% ( P <0.001), chronic obstructive pulmonary disease ( P =0.045), renal insufficiency ( P =0.002), Staphylococcus spp. ( P =0.032), and Streptococcus spp. ( P =0.013) as independent risk factors for 30-day mortality. Independent risk factors for 1-year mortality were identified as: age ( P <0.001), female sex ( P =0.018), diabetes ( P =0.018), preoperative stroke ( P =0.039), chronic obstructive pulmonary disease ( P =0.001), preoperative dialysis ( P <0.001), and valve vegetations ( P =0.004). Staphylococcus endocarditis is associated with an almost twice as high 30-day mortality and significantly inferior long-term outcome compared with IE by other commonly causative bacteria. Patients with Staphylococcus infection are more often female and critically ill, with >50% of these patients suffering from clinically relevant septic embolism. Early diagnosis and referral to a specialized center for surgical treatment are strongly recommended to reduce the incidence of preoperative deterioration and stroke due to septic embolism.