Neurologic syndromes often complicate the management of infective endocarditis (IE). We retrospectively reviewed 166 episodes of native valve endocarditis to assess the occurrence and implications of nonfocal encephalopathy, meningitis, salient headache, back pain, and brain abscess. Neurologic complications occurred in 35% (58/166) of patients: 41% (54/133) of mitral or aortic valve IE and 12% (4/33) of tricuspid valve IE. Of 133 cases of mitral or aortic valve IE, encephalopathy occurred in 14%, meningitis in 5%, and salient headache in 3%. All neurologic complications occurred more often with Staphylococcus aureus infection (67%) than with viridans streptococci (22%), including encephalopathy (22% versus 7%), meningitis (17% versus 0%), stroke (39% versus 16%), and death (39% versus 9%). Encephalopathy was associated with virulent organisms, increased patient age, and uncontrolled infection. Clinical, radiologic, and neuropathologic data all suggest that infective microemboli are often etiologic in IE-related encephalopathy. There were no macroscopic brain abscesses clinically identified. Meningitis occurred only with virulent organisms. While many clinical aspects of IE have changed in recent years, the frequency and gravity of neurologic complications have not.