Inconsistencies across studies on the association of environmental tobacco smoke (ETS) and pulmonary function may be clarified addressing potentially susceptible subgroups. We determined the association of ETS exposure at work with FVC, FEV1, and FEF25-75% in life-time never smokers (N = 3534) of the SAPALDIA random population sample (age 18-60). We considered sex, bronchial reactivity, and asthma status as a priori indicators to identify susceptible riskgroups. The multivariate regression models adjusted for height, age, education, dust/aerosol exposure, region, and ETS at home. Overall, ETS was not significantly associated with FVC (0.7%; -0.4 to +1.8), FEV1 (-0.1%; 95% CI: -1.3 to +1.1) or FEF25-75% (-1.9%; -4.2 to +0.5). Effects were observed among asthmatics (n = 325), FEV1 (-4.8%; 0 to -9.2); FEF25-75% (-12.4%; -3.7 to -20.4); FVC: (-1.7%; +2.1 to -5.5), particularly in asthmatic women (n = 183): FVC -4.4% (-9.6 to +1.1); FEV1: -8.7% (-14.5 to -2.5); FEF25-75%: -20.8% (-32 to -7.6), where duration of ETS exposure at work was associated with lung function (FEV1 -6% per hour of ETS exposure at work (p = 0.01); FEF25-75%: -3.4%/h (p < 0.05). In non-asthmatic women (n = 1963) and in men no significant effect was observed. The size of the observed effect among susceptible subgroups has to be considered clinically relevant. However, due to inherent limitations of this cross-sectional analysis, selection or information biases may not be fully controlled. For example, asthmatic women reported higher ETS exposure at work than asthmatic men. Given the public health importance to identify susceptible subgroups, these results ought to be replicated.