In this cross-sectional study, we investigated the association between occupational exposures and sickness absence (SA), the mediating role of respiratory symptoms, and whether genetic susceptibility to SA upon occupational exposures exists. Logistic regression was used to examine associations and structural equation modelling was used for mediation analyses. Genetic susceptibility was investigated by including interactions between occupational exposures and 11 candidate single nucleotide polymorphisms (SNPs). Biological dust, mineral dust, and pesticides exposure were associated with a lower prevalence of any SA (OR (95% CI) = 0.72 (0.58-0.89), 0.88 (0.78-0.99), and 0.70 (0.55-0.89), respectively) while gases/fumes exposure was associated with a higher prevalence of long-term SA (1.46 (1.11-1.91)). Subjects exposed to solvents and metals had a higher prevalence of any (1.14 (1.03-1.26) and 1.68 (1.26-2.24)) and long-term SA (1.26 (1.08-1.46) and 1.75 (1.15-2.67)). Chronic cough and chronic phlegm mediated the association between high gases/fumes exposure and long-term SA. Two of 11 SNPs investigated had a positive interaction with exposure on SA and one SNP negatively interacted with exposure on SA. Exposure to metals and gases/fumes showed a clear dose-response relationship with a higher prevalence of long-term SA; contrary, exposure to pesticides and biological/mineral dust showed a protective effect on any SA. Respiratory symptoms mediated the association between occupational exposures and SA. Moreover, gene-by-exposure interactions exist.