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Abstract Background Neglected tropical diseases (NTDs), such as leprosy and lymphatic filariasis (LF), can cause disabilities despite available treatment. Both diseases disproportionately affect India’s poorest populations, with high numbers in Jharkhand and Uttar Pradesh. Those affected experience severe psychosocial consequences, including participation restrictions, depression, and poor mental health. This study investigates the extent to which stigma affects social participation and mental wellbeing among persons with leprosy- and LF-related disabilities in two Indian states. Methodology In a cross-sectional design in Bokaro (Jharkhand) and Jaunpur (Uttar Pradesh), participants were randomly selected among persons with leprosy- or LF-related disabilities, along with comparable non-affected community members. Sociodemographic and disability data were collected, alongside four measures assessing mental wellbeing, depression, participation restriction, and stigma. Analysis used descriptive statistics, univariate, and multivariate regression. Results A total of 201 persons with leprosy-related disabilities, 240 with LF-related disabilities, and 98 non-affected community members were included. Persons with NTD-related disabilities exhibited significantly higher depression and participation restriction and reported lower mental wellbeing compared to community members (p<0.001). In the leprosy group, lower education and lower stigma were key determinants of mental wellbeing (R²=0.3), while in the LF group, higher age and less severe lymphoedema grade were significant (R²=0.5). Participation restriction was associated with higher age, poorer mental wellbeing, and depression in the leprosy group (R²=0.7), and with depression and stigma in the LF group (R²=0.6). Conclusion Persons with leprosy and LF-related disabilities face significant psychosocial challenges, including poor mental wellbeing, depression, and restrictions in participation, often exacerbated by stigma. Addressing these challenges requires integration of mental health support and stigma reduction within NTD programmes, with specific attention to the needs of persons with disabilities. Further research into connections between education, disability, and mental health is essential to deepen understanding and inform development of more targeted, effective interventions. Key Messages What is already known on this topic Leprosy and lymphatic filariasis (LF) are Neglected Tropical Diseases (NTDs) that can cause long-term physical impairments and are linked to stigma, discrimination, and poor mental health. However, the associations between these psychosocial factors have been underexplored and are often not addressed in disease programmes. What this study adds This study shows that persons affected by leprosy and LF in India experience worse mental wellbeing and greater participation restrictions than community members, with stigma playing a key role. Leprosy-affected participants reported higher overall stigma than those with LF. How this study might affect research, practice or policy The findings highlight the importance of integrating stigma reduction and mental health support into NTD programmes. Peer-led approaches like Basic Psychological Support for persons affected by NTDs (BPS-N) offer a promising model for improving psychosocial outcomes.