Background Homozygous sickle cell disease (SCD) compounded with bacterial endocarditis makes open-heart surgery a multidisciplinary challenge. Case description A 45-year-old African male patient with homozygous SCD presented with right heart decompensation, tricuspid regurgitation, and endocarditis of the aortic valve. Blood coulters were positive for coagulase-negative staphylococci. An emergent double valve replacement was successfully performed involving a multidisciplinary team. Conclusion Homozygous SCD is associated with an increased risk of preoperative vaso-occlusive complications. Surgery with cardiopulmonary bypass can be performed, if hypothermia, hypoxia, acidosis, or low-flows are being avoided. Due to the lack of data, the adequate approach is still intuitive and requires standardization.