Abstract Background Lack of social connections has a serious impact on health, increasing the risk of medical conditions such as depression, dementia, and coronary heart disease. However, evidence is limited by a disease-specific focus. We aimed to provide a comprehensive overview of differences in incidence rates of a broad range of medical conditions according to social disconnectedness (i.e., loneliness, social isolation, and low social support). Methods We conducted a cohort study using data on loneliness, social isolation, low social support, and a composite measure from the 2013 and 2017 Danish National Health Survey. Survey data was linked with register data on 11 categories of medical conditions through 2021. Poisson regression was applied to estimate incidence rate ratios (IRRs), incidence rate differences, and explore interaction with pre-existing mental disorders. Results Among 162,497 survey participants, 7.6%, 3.5%, and 14.8% were identified as lonely, socially isolated, and with low social support, respectively. Lonely individuals and individuals with low social support had a higher incidence rate of all 11 categories of medical conditions (interquartile range of IRRs, loneliness 1.22-1.49 and low social support 1.10-1.14), whereas this was the case for nine categories among socially isolated individuals (interquartile range of IRRs, 1.01-1.31). Applying the composite measure, the highest IRR was 2.61 (95% CI, 2.34-2.88) for a mental disorder and the lowest 1.03 (95% CI, 0.95-1.10) for cancer. We found neither major sex differences nor substantial interaction with pre-existing mental disorders. Conclusions Our study confirms and extends the available evidence on social disconnectedness and the risk of medical conditions. The attained knowledge may be of significance for mapping group-specific preventative needs and guiding interventions and health practitioners aiming to reduce the disease burden among socially disconnected individuals. Key messages • Based on survey and register data from 162,497 individuals, our study suggests that social disconnectedness, especially loneliness, is a determinant of a broad range of medical conditions. • The findings may be of importance for identifying and targeting the disease burden among socially disconnected individuals.