Purpose <p>The objective of this study was to analyze the association between mean PM_2.5 levels from 2000 to 2020 and the prevalence of epidermal growth factor receptor (<i>EGFR</i>) mutations worldwide.</p> Patients and methods <p>We fitted linear regression models weighted by the total number of non-small cell lung cancer (NSCLC) to estimate the association strength. Adjusted R² values were calculated, with values closer to 1 indicating a stronger association. Data from sixty-nine countries were available. PM_2.5 data for 2015‒2020 were obtained from the Organisation for Economic Co-operation and Development database (<a href="https://stats.oecd.org/">https://stats.oecd.org/</a>). Mean PM_2.5 levels, <i>EGFR</i> mutation prevalence data, and total NSCLC cases were acquired from published literature and national cancer registries.</p> Results <p>The association between PM_2.5 levels and EGFR-mutant prevalence ranged between moderate and weak (<i>R</i>² = 0.34, 95% Confidence interval [CI] 0.02‒0.67). The association further weakened (<i>R</i>² &lt; 0.15 in all comparisons) when stratified by area (European, Asian, or Latin American). Although certain countries had high air pollution and EGFR-mutant lung cancer prevalence (China: PM_2.5, 46.9% and 45.7%, respectively), the association was inconsistent.</p> Conclusions <p>The discrepancy between PM_2.5 levels and the prevalence of EGFR-mutant lung cancer could be attributed to differences in access to lung cancer genomic profiling, potential over- or underestimation of EGFR-mutant prevalence, non-homogeneous PM_2.5 levels within countries, inclusion of all patients with lung cancer regardless of smoking patterns, and other factors, such as genomic background and ancestry. These factors should be considered as potential limitations in directly associating PM_2.5 with EGFR-mutated lung cancer development.</p>