Purpose: Sickle cell anemia (SCA) is a monogenic disorder caused by a single point mutation in the beta-globin gene, however, phenotypic heterogeneity is commonly observed among the patients. Severity scores such as Tweel’s score were developed to differentiate SCA patients into various categories and identify severe patients who may need more clinical attention and management. However, most of these studies are conducted in Europeans and its utility has never been tested in Indian patients who are known to have a different clinical course and complications. We investigated the utility of the existing Tweel’s score comprising of 16 parameters in determining disease severity and further understand any differences to develop a severity score that can be applied for making informed management decisions Materials and methods: One of the severity scores proposed by Tweel et al, reported for the SCA patients, uses multiple clinical and biochemical parameters to categorize the severity. Using this scoring system, we used data on clinical history, course and complications and various biochemical parameters from 171 Indian Sickle cell anemia patients recruited at Government Medical College and Hospital. The patients were identified as mild, moderate and severe based on the clinician’s assessment (DJ and SI). The patients were also scored using the 16 parameters included in this score and allocated into three categories; mild, moderate and severe. Correlation analysis was performed to evaluate the performance of the established scoring system with the clinical assessment in Indian patients. Further, various combinations of clinical course and biochemical parameters were used and correlation analysis was performed. Results: Approximately, 2/3rd of the patients (64.9%) identified as per clinicians’ assessments were correctly matched with those using Tweel’s scoring system, leaving one-third still uncategorized. Further, mild cases formed the majority of the concordant patients compromising the correct categorization of moderate and severe patients. Modified scores were generated by including in Tweel’s score, four clinical parameters as per the treating physician’s experience (MS1) and further, replacing the biochemical measures with clinical parameters based on clinical course and complications (MS2). Scores were recalculated for the Discovery group using two new scoring systems. Comparison of the modified scores with the standard Tweel’s score improved the disease severity prediction to 88.7% for severity scores having both clinical and biochemical parameters (MS1) and up to 92.3% using only clinical course and no biochemical parameters (MS2). Results were found to be robust even after designing and comparing several random sets of Discovery and validation groups from the 171 patients included in the study, as well as swapping the discovery group with the validation group for all random sets. Conclusion: We have developed a severity score for Indian sickle cell patients which could be used for better understanding and evaluation of the clinical course and hence disease management. This will help clinicians being able to evaluate sickle cell anemia patients and manage them accordingly. The authors do not declare any conflict of interest