Background: Cases of infective endocarditis (IE) with >30 mm vegetations are rare and are associated with high mortality. Clinical experience, clear therapeutic standards, and outcome evidence about these cases are still lacking. Methods: Detailed clinical data from patients suffering from IE complicated with >30 mm vegetations were collected from a hospital medical record system. Age- and sex-matched IE cases with 10–20 mm vegetations were used as a control group. Results: Twenty-two patients with >30 mm IE vegetations confirmed by biopsy and transthoracic echocardiography (TTE) were included. Thirteen (59.0%) patients had basic cardiac diseases, mainly congenital heart disease (CHD), rheumatic heart disease, and device-related issues. Fever (81.8%), heart murmur (86.4%), heart failure (86.4%), and embolism (50.0%) were common clinical manifestations and complications. TTE showed the diameter of vegetations was 34.5 (30.0–39.8) mm. The vegetations were usually accompanied by severe valvular regurgitation and pulmonary hypertension, and were most often located in the mitral valve (38.4%). Laboratory examinations indicated anemia, hypoalbuminemia, heart failure and inflammation. The rate of positive blood culture was 68.2%. Streptococcus viridans was the most frequent pathogen (26.7%). All individuals underwent vegetectomy and valve replacement or repair surgery, within 2 days of diagnosis. Compared with 10–20 mm vegetations group, >30 mm vegetations group had more complicated basic cardiac diseases, more special microbial infection, higher levels of procalcitonin (PCT) and D-dimer, more common heart failure and embolism. They received more biological valve replacements, and had longer intensive care unit length of stay (ICU-LOS). A few patients developed significant postoperative adverse events, including intracerebral hemorrhage (ICH), septic shock, and new symptomatic thrombosis. Re-exploratory thoracotomy was performed in two cases. All patients survived during 6-month follow-up without IE recurrence in >30 mm vegetations group, while there was one death and one recurrence in the 10–20 mm vegetations group. Conclusions: For IE complicated with >30 mm vegetations, clinical characteristics are diverse and vegetations on TTE are prone to misdiagnosis as thrombus or tumors. This article also emphasizes the use of >30 mm IE vegetations as an independent indication for early surgery to improve prognosis.