'Lung cancer associated with cystic airspaces' is a rare radiological entity that is more frequently encountered on imaging studies and is gaining more attention since the widespread use of CT for lung cancer screening. Numerous aspects of this entity remain unraveled, including molecular profiling. The goal of this observational retrospective single-center case series is to investigate the molecular profile of lung cancers presenting with this specific morphology in a Caucasian population. Between January 2014 and May 2017, 13 patients were presented at the Multidisciplinary Thoracic Oncology Tumor Board with imaging findings consistent with 'lung cancer associated with cystic airspaces'. Electronic medical files were reviewed for patient characteristics, stage, histopathological findings and - in particular - molecular profiling. Histopathological diagnosis showed adenocarcinoma in 11 patients in our series. Mutational analysis in 10 showed different molecular alterations: an EGFR exon 18 mutation, ROS1 rearrangement and BRAF mutation in one patient each. Two patients showed KRAS mutations. With 5 out of 10 patients with an adenocarcinoma presenting with cystic airspace morphology showing a molecular alteration, this may indicate that in this subgroup, molecular profiling is mandatory, regardless of smoking history.