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Background Cities face rapid changes leading to increasing inequalities and emerging public health issues that require cost-effective interventions. The urban exposome concept refers to the continuous monitoring of urban environmental and health indicators using the city and smaller intra-city areas as measurement units in an interdisciplinary approach that combines qualitative and quantitative methods from social sciences, to epidemiology and exposure assessment. Methods In this proof of concept study, drinking water and quality of life indicators were described as part of the development of the urban exposome of Limassol (Cyprus) and were combined with agnostic environment-wide association analysis. This study was conducted as a two-part project with a qualitative part assessing the perceptions of city stakeholders, and quantitative part using a cross-sectional study design (an urban population study). We mapped the water quality parameters and participants’ opinions on city life (i.e., neighborhood life, health care, and green space access) using quarters (small administrative areas) as the reference unit of the city. In an exploratory, agnostic, environment-wide association study analysis, we used all variables (questionnaire responses and water quality metrics) to describe correlations between them. Results Overall, urban drinking-water quality using conventional indicators of chemical (disinfection byproducts-trihalomethanes (THM)) and microbial (coliforms, E. coli, and Enterococci) quality did not raise particular concerns. The general health and chronic health status of the urban participants were significantly (false discovery rate corrected p-value < 0.1) associated with different health conditions such as hypertension and asthma, as well as having financial issues in access to dental care. Additionally, correlations between THM exposures and participant behavioral characteristics (e.g., household cleaning, drinking water habits) were documented. Conclusion This proof-of-concept study showed the potential of using integrative approaches to develop urban exposomic profiles and identifying within-city differences in environmental and health indicators. The characterization of the urban exposome of Limassol will be expanded via the inclusion of biomonitoring tools and untargeted metabolomics.