Objective: Currently, unlike earlier years, patients affected by multiple primary malignancies (MPM) are significantly increased, thus representing a clinical-pathologic category worthy of attention. Their clinical features and prognosis still need to be studied thoroughly, and this is the aim of our study. Methods: Patients with MPM involving lung cancer admitted in our center between January 2006 and December 2016 were considered. Parametric and nonparametric testing was used for statistical comparisons. Univariate and multivariate analysis was used to evaluate the variables associated with a prognostic value. Results: MPM incidence was 19.8%. Among the 222 patients with MPM enrolled, 204 (91.8%) had two malignancies, while 18 (8.2%) had three malignancies, 38 (17.1%) were synchronous, 41 (18.5%) had lung cancer first (LCF) and 181 (81.5%) had other cancer first (OCF). A significant difference between the time of first cancer diagnosis to the second cancer diagnosis in the LCF vs OCF group was found (median 32 vs 51 months; p-value: 0.038). The most frequent anatomical sites of malignancies preceding or following lung cancer were prostate, colorectal, bladder, and larynx. Multivariate analysis revealed that sex, histologic pattern, and time and order of occurrence were independent factors for overall survival, with male sex, squamous cell lung carcinoma, synchronous and LCF MPM significantly associated with poorer overall survival. Conclusions: Prostate, colorectal, bladder, and larynx were the most frequent anatomical sites of malignancies preceding or following lung cancer. Male sex, squamous cell lung carcinoma, synchronous and LCF MPM might be associated with poorer prognosis.