OBJECTIVES: To examine the association between antidepressant drug use and  C – Reactive Protein (CRP) among adults with inflammatory medical conditions after controlling for gender, race, age, income, Non-steroidal anti-inflammatory drug use, smoking, perceived health status, alcohol use and physical activity. METHODS: Retrospective cross-sectional study with linked data from laboratory, prescription medication, medical conditions and demographic files of the National Health and Nutritional examination Survey (NHANES). The study sample (N = 3,492) consisted of adults (≥20 years) with any inflammatory condition (arthritis, gout, chronic obstructive pulmonary diseases, asthma, coronary artery disease, diabetes, obesity, liver, or thyroid condition, cancer and stroke). Ordinary least square regression (OLS) and multinomial logistic regressions on low (< 1.0 mg/l), average (1-3 mg/l) and high (>3 mg/l) were used to analyze the association between antidepressant use and CRP. RESULTS: Antidepressant use was reported by 13% of the adults and the average CRP value for the sample was 4.85 mg/l (SE = 0.0113).  22% had low CRP, 33% had average CRP and 45% had high CRP values. Average CRP values were not statistically different between antidepressant users and non-users.  Other factors that were significantly associated with CRP were: perceived health status, smoking and income. For example, adults with excellent perceived health status had significantly lower CRP values (p <0.004) as compared to those with poor health status.  CONCLUSIONS: In this population-based study, no statistically significant association between antidepressant use and inflammatory bio-markers were found in individuals with an inflammatory condition. Future research may need to focus on specific inflammatory conditions including depression.