This study aimed at determining the diagnostic implications of indirect signs of infection at FDG-PET—i.e., hypermetabolisms of the spleen and/or bone marrow (HSBM)—when documented in patients with known or suspected infective endocarditis (IE). HSBM were defined by higher mean standardized uptake values comparatively to that of the liver on FDG-PET images from patients with a high likelihood of IE and prospectively included in a multicenter study. Among the 129 included patients, IE was ultimately deemed as definite in 88 cases. HSBM was a predictor of definite IE (P = 0.014; odds ratio (OR) 3.2), independently of the criterion of an abnormal cardiac FDG uptake (P = 0.0007; OR 9.68), and a definite IE was documented in 97% (29/30) of patients showing both HSBM and abnormal cardiac uptake, 78% (7/9) of patients with only abnormal cardiac uptake, 67% (42/63) of patients with only HSBM, and 37% (10/27) of patients with neither one. In this cohort with a high likelihood of IE, HSBM is an additional albeit indirect sign of IE, independently of the criterion of an abnormal cardiac uptake, and could reinforce the suspicion of IE in the absence of any other infectious, inflammatory, or malignant disease.