Smoking is one of the most important preventable causes of chronic disease and premature death in adults worldwide. The effect of smoking on blood parameters is not well known, and the results are contradictory. The present study aimed to investigate the association between smoking status and blood parameters of adults in southwestern Iran. This cross-sectional study was conducted using data from the recruitment phase of the Fasa Adults Cohort Study (FACS). A total of 6988 adults participated. The study variables included demographic characteristics, chronic diseases, smoking status, physical activity, and blood cell parameters. Linear regression analyses were performed to examine associations between smoking status and blood parameters. Based on the multivariate linear regression results, current smokers showed higher levels of white blood cells (β = 0.89), hemoglobin (β = 0.14), mean corpuscular volume (β = 1.05), lymphocyte/monocyte ratio (β = 0.75), mean corpuscular hemoglobin concentration (β = 0.18), and mean corpuscular hemoglobin (β = 0.50) compared to non-smokers. Additionally, mean platelet volume was significantly lower in ex-smokers (β = – 0.05) and passive smokers (β = – 0.05) compared to never-smokers. Our results indicate that cigarette smoking is linked to increased levels of specific blood cell parameters. Although smoking clearly affects various hematological measures, inconsistencies in the literature-particularly concerning indices like MPV-highlight the need for more detailed research.