Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear. We aimed to determine the incidence of nodules considered for invasive biopsy and evaluate the final diagnoses and procedure-related complications in never-smokers in comparison to ever-smokers who underwent LDCT screening.We evaluated 37 436 asymptomatic adults (17 968 never-smokers and 19 468 ever-smokers) who underwent LDCT screening for lung cancer between January 2009 and December 2018 at a tertiary centre in South Korea. The rates of invasive diagnostic procedures for detected nodules and related complications, and the diagnostic outcomes were determined in the never-smoker and ever-smoker groups.Among the never-smokers, 2908/17 968 (16.2%) had positive nodules. Overall, 139/17 968 (0.77%) never-smokers and 194/19 468 (1.00%) ever-smokers underwent invasive biopsy (p=0.022). Lung cancer was diagnosed in 84/17 968 (0.47%) of never-smokers and 123/19 468 (0.63%) of ever-smokers (p=0.032). The proportions of participants diagnosed with benign disease after invasive biopsy (false-positive) were 50/17 968 (0.28%) and 69/19 468 (0.35%) in the never-smoker and ever-smoker groups (p=0.191). Multivariate analyses revealed no significant associations of smoking with the risk of a false-positive diagnosis (OR=0.98, 95% CI=0.62-1.57) and complications (OR=1.33, 95% CI=0.65-3.73) after biopsy. Of the 84 never-smokers with lung cancer, 82/84 (97.6%) had adenocarcinoma, and 75/84 (89.3%) were in stage I with a favourable prognosis.LDCT screening in never-smokers resulted in a notable detection rate of lung nodules, which warranted invasive biopsy. The lung cancer detection rate was lower in never-smokers than in ever-smokers. However, no significant differences in the false-positive and complication rates were observed between the two groups. Accordingly, a more specifically tailored management strategy is needed for screen-detected nodules in Asian never-smokers.