Background: Lu6 is a high-incidence antigen of the Lutheran blood group. Examples of anti-Lu6 are rare and are of uncertain clinical significance. CASE REPORT: Three patients were encountered in whom anti-Lu6 was detected on pretransfusion screening. The patients were all Iranian Jews and were not known to be related. In vitro studies to ascertain the potential clinical significance of the antibody using the monocyte monolayer assay (MMA) were negative in two patients. The third patient received a two-unit transfusion of incompatible Lu6 RBCs with no signs of hemolysis. However, after the transfusion, the MMA and a chemiluminescence test were positive, whereas a chromium survival study was normal. Thus, the antibody may have changed in its clinical significance. CONCLUSION: Although anti-Lu6 does not appear to be a clinically significant RBC antibody in all circumstances, transfusion of Lu6 RBCs in patients with anti-Lu6 should be performed cautiously.