Simple SummaryLung cancer is a heterogeneous group of diseases in both morphology and molecular subtypes. There are two main histological categories of lung cancer: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Although overall lung cancer mortality is declining in Italy, little is known about mortality trends by cancer subtype at the population level because death certificates do not record subtype information. This observational epidemiological study, using data from the Reggio Emilia Cancer Registry, evaluated the incidence, mortality, and survival trends of lung cancer according to the specific subtype. This study confirms the decline in the incidence and mortality of lung cancer in males, mainly squamous cell forms, inversely associated with cigarette smoking and the introduction of new drugs since 2013.AbstractThis study assessed the incidence, mortality, and survival of lung cancer subtypes of NSCSLC (non-small-cell lung cancer), SCLC (small-cell lung cancer), and other morphologies. It is an observational epidemiological study using 7197 cases from the Reggio Emilia Cancer Registry recorded between 2001 and 2020 in males and females. The incidence of NSCLC in 5104 males indicates a significant 3% annual increase until 2013 and then a decline of −3.2% that is not statistically significant; until 2014, mortality increased significantly (3.2%), but it then decreased non-significantly (−12.1%), especially squamous cell cancer. In 2093 females, the incidence and mortality trends continued to rise significantly through 2012, and then they began to slightly decline (not statistically significant). The two-year relative survival of NSCLC increased from 32% to 38% in males and from 42% to 56% in females. SCLC in males decreased significantly both in incidence and mortality, while in women, it showed a slight increase (significantly for incidence but not for mortality). This study is important because it analyzes the decrease in lung cancer in males and the increase in females in relation to the different histotypes. Our study’s findings confirmed a decline in male incidence and death beginning in 2013. We were unable to determine if the drop in cigarette smoking and the introduction of new drugs such as EGFR in first-line therapy were responsible for the lower incidence.