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Waterpipe (WP) smoking is a global phenomenon, with the most consumers in Middle East countries and China. Heavy metals exposure related to WP smoking has been associated with many adverse health effects. However, the association of lifestyle factors and smoking habits with blood heavy metals concentration in WP smokers is unclear yet. Therefore, we aimed to investigate the relationship of lifestyle factors (i.e., diet and physical activity) and smoking habits (i.e., duration of the use of WP and times of smoking WP per week) with blood concentrations of lead (Pb) and cadmium (Cd). This cross-sectional study was based on 86 WP smokers in Khalkhal, Iran (2018). Graphite furnace atomic absorption spectrometry (GFAAS) was used to measure heavy metals. The median (interquartile range (IQR)) of Pb and Cd concentrations were 39 (24) and 1.3 (1.2) μg/L. The blood Pb and Cd levels were significantly higher in participants with lower education level (P-value = 0.049 and 0.041, respectively). An IQR increase in physical activity per week was associated with −0.12 μg/L (95% confidence interval (CI): −0.23, −0.01, P-value = 0.04) decrease in Pb concentration. An increase in the times of consuming fruit per week was negatively associated with the concentration of Cd. Overall, our findings suggested that physical activity and healthy diet have been associated with lower blood heavy metal concentrations in WP smokers; however, further studies are needed to confirm these findings. • Blood levels of Pb and Cd were measured in waterpipe smokers. • Higher physical activity per week was associated with lower Pb concentration. • An increase in the times of consuming fruit per week was negatively associated with the Cd concentration. • The times of smoking WP per week was positively associated with Cd concentration. • Duration of the use of WP smoking was positively associated with Pb concentration. [ABSTRACT FROM AUTHOR]