Despite known use of antibody screening (AS), it has not been adopted uniformly across blood centers in India. Many centers in India are currently using a type and hold policy with subsequent antihuman globulin (AHG) crossmatch when blood units are requested. The main aim of this study was to assess the benefits of a type and screen (TS) policy in which blood grouping and AS are performed simultaneously during the first hospital visit. If the AS is negative, subsequent requests for blood units would require an immediate spin test (IST) crossmatch with release of blood units, followed by an AHG crossmatch. This prospective, observational study was conducted at a tertiary health care center between July 2014 and December 2018 and included only Indian patients. Blood grouping and AS were performed during the first hospital visit on a total of 22,888 patients; the majority of patients were from hemato-oncology and blood marrow transplant, hepatology and liver transplant, cardiothoracic vascular surgery, and medical intensive care units. Demographic parameters were evaluated for risk of alloimmunization, and a record of the same was maintained. Depending on the AS results, a further course of action was chosen. Clinically significant alloantibodies were detected in 145 patients, and autoantibodies were detected in 53 patients. Alloantibodies were mainly against Rh and Kell blood group antigens. A significantly higher proportion of patients in the AS+ group required blood transfusion when compared with the AS- group. In cases wherein the IST crossmatch was compatible but AHG crossmatch was not, follow-up did not demonstrate any clinical or laboratory evidence of hemolysis. AS is a safe, efficient, and beneficial tool for pretransfusion compatibility testing in both AS+ and AS- patients. With a TS policy, AHG crossmatch can be omitted in AS- patients without compromising safety.