Background: This is an observational study aimed at analysing the incidence trends of 18 different types of cancer, classified by site, in a population cohort of over 4 million residents in the Veneto region of north-eastern Italy over a period of almost 30 years. Methods: This population-based observational study is based on epidemiological data on cancer incidence collected by the Veneto Regional Cancer Registry for the years 1987-2018. A joinpoint regression analysis was performed to identify significant changes in annual cancer incidence (Annual Percent Change - APC) by sex and tumour site. The average Annual Percent Change (APC) was also calculated for each trend. Results: Overall, the APC of all cancers (excluding non-melanoma skin cancer) shows significant differences between the sexes (-1.7 males, -0.9 females). In addition, the APC of the incidence of tumours, classified by site, shows differences between males and females in 9 tumours (brain, larynx, lung, skin melanoma, oesophagus, colorectum, liver, bladder and oral cavity), while the remainder show similar trends (thyroid, stomach, pancreas, biliary tract, kidney and urinary tract, leukaemia, multiple myeloma non-Hodgkin lymphoma, Hodgkin lymphoma). Conclusions: This study has shown that sex differences in cancer incidence trends still remain of concern for several malignancies. These observations should guide policy makers to adopt differentiated strategies to maximise the effectiveness of primary and secondary prevention.