To date, there have been no well-organized clinical studies evaluating which air pollutants affect dry eye disease (DED). In this study, we investigated changes in the clinical parameters of DED according to exposure to outdoor air pollutants, including PM (particulate matter with an aerodynamic diameter of less than 2.5 μm), PM (less than 10 μm), and ozone. A prospective observational study was conducted on 43 DED patients who had used the same topical eye drop treatment between 2016 and 2018 in South Korea. Ocular surface discomfort index (OSDI) score, tear film break-up time (TBUT), corneal fluorescein staining score (CFSS), and tear secretion were measured during each visit. Air pollution data of ambient PM, PM, and ozone, based on the patients’ address, were obtained, and mean concentrations were computed for one day, one week, and one month before the examination. The relationships between air pollutants and DED were analyzed in single- and multi-pollutant models adjusted for demographic and clinical factors. In the multi-pollutant model, the OSDI score was positively correlated with ozone and PM exposure [ozone: β(exposure for 1 day/1 week) = 0.328 (95% CI: 0.161-0.494)/0.494 (0.286-0.702), p < 0.001/<0.001, per 1 ppb increase; PM: β(1 day/1 week) = 0.378 (0.055-0.699)/0.397 (0.092-0.703), p = 0.022/ = 0.011, per 1 μg/m increase], and tear secretion decreased with increased ozone exposure [ozone: β(1 week/1 month) = -0.144 (-0.238 to -0.049)/-0.164 (-0.298 to -0.029), p = 0.003/ = 0.017, per 1 ppb increase]. Interestingly, increased PM exposure was only associated with decreased TBUT [β(1 day/1 week/1 month) = -0.028(-0.045 to -0.011)/-0.029(-0.046 to -0.012)/-0.023(-0.034 to -0.006), p = 0.001/ = 0.001/ = 0.018, per 1 μg/m increase]. Tear secretion and CFSS were not associated with PM exposure. Increased ozone and PM exposure led to aggravated ocular discomfort, and increased PM concentration aggravated tear film stability in patients with DED. Thus, each air pollutant may aggravate DED via different mechanisms of action.Copyright © 2020 Elsevier Ltd. All rights reserved.