Lewis antibodies, such as anti-Lea and anti-Leb, are commonly encountered in routine immunohematology. They are typically IgM in nature and are generally considered clinically insignificant, as they rarely cause hemolytic transfusion reactions (HTRs) or hemolytic disease of the fetus and newborn (HDFN). However, rare cases have been reported where anti-Lewis antibodies caused mild transfusion reactions. In this case report, we describe a 69-year-old male with sepsis secondary to a neck carbuncle who was found to have clinically significant anti-Lewis antibodies. These antibodies presented a challenge during crossmatching, as only two out of seven units of packed red blood cells were compatible. This case underscores the importance of thorough pre-transfusion testing to ensure safe and effective blood transfusion practices.