The study objective was to assess the association between prescription NSAIDs and depression among adults with inflammatory chronic conditions. Some randomized clinical trials have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) can be beneficial in reducing depressive symptoms among adults with depression. As depression is often considered as an inflammatory disease, NSAIDs may also reduce the risk of depression by reducing inflammation. We used a retrospective cross-sectional design. Data were derived from 2015 Medical Expenditure Panel Survey (MEPS), a nationally representative sample of the US non-institutionalized civilian population. Inflammatory conditions included arthritis, asthma, cancer, cardiovascular disease, chronic obstructive pulmonary disease (COPD), and diabetes. The dependent variable was the presence or absence of depression and the key independent variable was prescription NSAIDs use. Logistic regression models were used to examine the adjusted associations between NSAIDs and depression. In these regressions, other independent variables (biological, sociocultural, socio-economic, access to healthcare services, medical conditions, behavioral and environmental factors) that may affect the relationship between NSAIDs and depression were also included. All analyses accounted for the complex survey design of MEPS. The study sample consisted of 11,714 adults, representing approximately 124.5 million adults with inflammatory conditions. Overall, 18.2% reported depression and 21% used prescription NSAIDs. A higher percentage of adults using NSAIDs reported depression compared to those without NSAIDS use (23.5% vs 16%;OR=1.59;95%CI=1.40,1.82). In the fully-adjusted logistic regression model, with controls for biological (sex, age, race/ethnicity), sociocultural, socio-economic, access to healthcare services, medical conditions including pain, behavioral and environmental factors, adults using prescription NSAIDs had higher odds of depression (AOR=1.24;95%CI=[1.07,1.43]) compared to those without NSAIDs. In this first real-world study of all adults (with and without depression) in the US, we observed a positive association between prescription NSAIDs and the presence of depression.