Professional exposures to respirable dusts from phosphate mines are associated with the development of an inflammatory response and airways diseases. This study was performed on 12 phosphate workers versus 8 unexposed controls, including smokers and non-smokers. It consisted of assessing the incidence of phosphate dusts exposure associated or not with smoking on the plasmatic inflammatory status of phosphate mine workers versus controls. The following parameters were studied: hematological profile and plasma level of seven cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, tumor necrosis Factor (TNF-α), macrophage inflammatory protein (MIP-1β)) and two eicosanoids (leucotriene B-4 (LTB-4) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE)) measured by a multiplexed flow cytometric method (CBA: Cytometric Bead Array) or ELISA. In phosphate workers, mainly smokers, the level of white blood cells (WBCs) and lymphocytes (LYM) was significantly higher as compared with controls. This was associated with enhanced levels of IL-1β, IL-6, IL-8, MIP-1β, and LTB-4. In smokers (including phosphate mine workers and controls), the level of LYM was also significantly higher than in controls. Based on a logistic regression analysis, smoker phosphate mine workers have a higher relative risk than controls to have an increase concentration of some cytokines, especially IL-1β, IL-6, IL-8, TNF-α, and MIP-1β. Moreover, the combined effect of smoking and phosphate dusts exposure increases the level of leucocytes as well as the concentration of IL-1β, IL-6, IL-8, MIP1-β, and LTB-4. The present study demonstrates that phosphate dusts are able to trigger a systemic inflammatory reaction characterized by enhanced levels of circulating immunocompetent cells, plasmatic cytokines and eicosanoids, and it establishes that these side effects are enhanced by smoking.