The MNS system is a highly complex blood group system encoded by the GYPA, GYPB and GYPE genes. The clinically significant 'S' and 's' antigens are thought to be absent if the 'U' antigen is absent on the RBCs. This leads to formation of the very rare S-s-U- phenotype attributed to mutations in the GYPB gene. Such individuals produce anti-U antibodies in a transfusion setting or pregnancy.Blood samples of an Indian antenatal women undergoing a twin pregnancy were referred to us for resolving the complex serology arising due to pan agglutination. Antibody studies revealed presence of anti-U and anti-D antibodies in the serum with titres less than ≤ 32 and the red cell antigen phenotype was found to be M-N + S-s-U-. Detailed molecular investigations revealed deletion of the GYPB gene as the causative agent. Direct agglutination test on both the babies' cells was positive indicating hemolytic disease of the newborn. One of the twin children was manage by exchange transfusion and other by phototherapy.In conclusion this is the first report on molecular investigations of the rare S-s-U phenotype. This study highlights the need for availability of rare cells and a national rare donor registry for transfusion management of patients with such rare blood types.