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Lung cancer presenting as subsolid nodule (SSN) can show slow growth, hence treating SSN is controversial. Our aim was to determine the long-term outcome of subjects with unresected SSNs in lung cancer screening.Since 2005, the Multicenter Italian Lung Detection (MILD) screening trial implemented active surveillance for persistent SSN, as opposed to early resection. Presence of SSNs was related to diagnosis of cancer at the site of SSN, elsewhere in the lung, or in the body. The risk of overall mortality and lung cancer mortality was tested by Cox proportional hazards model.SSNs were found in 16.9% (389 of 2303) of screenees. During 9.3 ± 1.2 years of follow-up, the hazard ratio of lung cancer diagnosis in subjects with SSN was 6.77 (95% confidence interval: 3.39–13.54), with 73% (22 of 30) of cancers not arising from SSN (median time to diagnosis 52 months from SSN). Lung cancer–specific mortality in subjects with SSN was significantly increased (hazard ratio = 3.80; 95% confidence interval: 1.24–11.65) compared to subjects without lung nodules. Lung cancer arising from SSN did not lead to death within the follow-up period.Subjects with SSN in the MILD cohort showed a high risk of developing lung cancer elsewhere in the lung, with only a minority of cases arising from SSN, and never representing the cause of death. These results show the safety of active surveillance for conservative management of SSN until signs of solid component growth and the need for prolonged follow-up because of high risk of other cancers.