Anti-C^w antibody is an immunoglobulin against the red cell antigen C^w which is a low frequency red cell antigen that belongs to the Rh antigen system. It is a clinically significant antibody and may cause haemolysis on exposure to antigen positive red cells. Due to its low frequency, it is not included in routine antibody screening panels. A 32 years healthy male donor with no history of transfusion donated whole blood at the department of Transfusion Medicine & Blood Centre of our institute. As a part of routine pre-transfusion testing, the donor’s samples were subjected to automated blood grouping and screening for unexpected red cell antibodies using 3 cells panel on solid-phase red-cell adherence (SPRCA) (Galileo Neo, Immucor, Norcross, USA). The antibody screening came out to be positive with a reaction in cell I of the antibody screening panel. Further the antibody was identified as anti C^w in using 16 cells panel, select cells and phenotyping. In the present case, the anti-C^w antibody was found to be reactive at 37⁰C and AHG phase which could lead to haemolytic transfusion reaction. The fact that the male donor had no history of transfusion or transplant led us to the conclusion that it was a naturally occurring, but a clinically significant antibody. This case highlights the importance of performing an antibody screening for healthy donors as well and urges transfusion services to procure screening cells which incorporate C^w positive cells.