Perifissural nodules (PFNs) are a common finding on chest CT, and are thought to represent non-malignant lesions. However, data outside a lung cancer-screening setting are currently lacking. In a nested case-control design, out of a total cohort of 16,850 patients >= 40 years of age who underwent routine chest CT (2004-2012), 186 eligible subjects with incident lung cancer and 511 controls without were investigated. All non-calcified nodules >= 4 mm were semi-automatically annotated. Lung cancer location and subject characteristics were recorded. Cases (56 % male) had a median age of 64 years (IQR 59-70). Controls (60 % male) were slightly younger (p<0.01), median age of 61 years (IQR 51-70). A total of 262/1,278 (21 %) unique non-calcified nodules represented a PFN. None of these were traced to a lung malignancy over a median follow-up of around 4.5 years. PFNs were most often located in the lower lung zones (72 %, p<0.001). Median diameter was 4.6 mm (range: 4.0-8.1), volume 51 mm3 (range: 32-278). Some showed growth rates < 400 days. Our data show that incidental PFNs do not represent lung cancer in a routine care, heterogeneous population. This confirms prior screening-based results. * One-fifth of non-calcified nodules represented a perifissural nodule in our non-screening population. * PFNs fairly often show larger size, and can show interval growth. * When morphologically resembling a PFN, nodules are nearly certainly not a malignancy. * The assumed benign aetiology of PFNs seems valid outside the screening setting.