Objective: Studying the association between the occupational exposure to Pb, As, Cd, and Cu with the serum levels of 2 novel biomarkers of cardiovascular stress; growth differentiation factor 15 and soluble suppression of tumorigenicity 2, in some Egyptian Cu smelter workers. Methods: Forty-one exposed workers and 41 administrative controls were clinically evaluated. Serum/blood levels of heavy metals and biomarkers were measured for both groups. Results: The smelter workers showed significantly elevated levels of heavy metals and biomarkers compared with controls. The elevated serum levels of both biomarkers were significantly and positively correlated with each other, the levels of heavy metals, and the duration of employment of the exposed workers. Conclusions: There was a significant association between the levels of heavy metals and both biomarkers among the smelter workers. Further prospective studies should be performed.