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Background and objective Sickle cell disease (SCD) is a genetic disorder of haemoglobin affecting red blood cells with the second highest burden in India. In this study, we examine the epidemiology of SCD in Chamarajanagar district, a largely rural south Indian district in Karnataka with a mixed rural tribal and non-tribal population to generate a more comprehensive understanding of the prevalence of SCD in southern India through the axes of social demographics.Methods We collected household and individual sociodemographic data and blood samples for determining SCD status using a cross-sectional study design among a subsample of consenting participants from forest-dwelling tribal communities and non-tribal communities. This study is nested in a previous study, ‘Towards Health Equity & Transformative Action on Tribal Health’, a multisite research study on tribal health inequities.Results Of the 547 study participants screened, 80 (14%) were found positive for the sickle cell allele and 238 (44%) were found anaemic. The association between selected sociodemographic characteristics and the sickle cell allele was also explored and presented for both scheduled tribes (STs) and non-ST populations.Interpretation and conclusions We observed a higher prevalence of sickle cell allele among people residing in tribal and remote villages. Although no significant association was found between sickle cell allele and demographics like sex, marital status and literacy, there was a considerable association between sickle cell allele and Socio-Geographical Disadvantage Index among ST and non-ST communities, the implications of which are discussed in the study.