Purpose:To assess the prevalence, natural course, and malignancy rate of perifissural nodules (PFNs) in smokers participating in a lung cancer screening trial.Materials and Methods:As part of the ethics-committee approved Dutch-Belgian Randomised Lung Cancer Multi-Slice Screening Trial (NELSON), computed tomography (CT) was used to screen 2994 current or former heavy smokers, aged 50-74 years, for lung cancer. CT was repeated after 1 and 3 years, with additional follow-up CT scans if necessary. All baseline CT scans were screened for nodules. Nodule volume was determined with automated volumetric analysis. Homogeneous solid nodules, attached to a fissure with a lentiform or triangular shape, were classified as PFNs. Nodules were considered benign if they did not grow during the total follow-up period or were proved to be benign in a follow-up by a pulmonologist. Prevalence, growth, and malignancy rate of PFNs were assessed.Results:At baseline screening, 4026 nodules were detected in 1729 participants, and 19.7\% (794 of 4026) of the nodules were classified as PFNs. The mean size of the PFNs was 4.4 mm (range: 2.8-10.6 mm) and the mean volume was 43 mm(3) (range: 13-405 mm(3)). None of the PFNs were found to be malignant during follow-up. Between baseline and the first follow-up CT scan, 15.5\% (123 of 794) were found to have grown, and 8.3\% (66 of 794) had a volume doubling time of less than 400 days. One PFN was resected and proved to be a lymph node.Conclusion:PFNs are frequently found at CT scans for lung cancer. They can show growth rates in the range of malignant nodules, but none of the PFNs in the present study turned out to be malignant. Recognition of PFNs can reduce the number of follow-up examinations required for the workup of suspicious nodules.A-A?A 1/2 RSNA, 2012.