A positive direct antiglobulin test has been reported in 1:1000 to 1:14,000 blood donors and 1-15 % of hospital patients. Drugs may cause a positive direct antiglobulin test result and/or immune-mediated haemolysis with an incidence of approximately 1 in a 1 million population. Our aim is to highlight the importance of following strict transfusion protocols and management insight in a direct antiglobulin test positive patient showing incompatibility with multiple units possibly due to drug induced immune haemolytic anaemia (DIIHA). We also aim to highlight importance of autologous blood transfusion in an orthopaedic procedure in which homologous transfusion may be needed. We are presenting case of a 36 year old male with alleged h/o of road traffic accident with comminuted intra-articular fracture of the distal femur. He had h/o of ankylosing spondylitis since last 20 years on medication with indomethacin and methotrexate. A review of the literature was performed which showed use of drug methotrexate as an uncommon clinical entity for DIIHA; sporadic reports exist in the medical literature to support this view. The review of the literature in combination with our own data showed methotrexate can be a cause of DIIHA. We therefore advocate proper immunohaematological work up and use of autologous blood for management of at-risk-patients of DIIHA.