Abstract Background Similar to other European countries, Italy's healthcare system is undergoing significant changes. Variations in ‘avoidable’ mortality (AM) may reflect such changes on management and quality of care. The aim of this study was to investigate the regional and gender-related trends of AM, and to provide evidence for addressing policy and reducing health disparities in Italy. Methods We conducted a 14-year time-trend analysis (2006-2019). Mortality and population data were obtained from the Italian Institute of Statistics. Bi-yearly age-standardized AM was calculated by gender and region, using the joint OECD/Eurostat list that includes both preventable and treatable causes of death. Results Overall, AM showed a significant reduction from 2006/7 to 2018/9 (221.0 vs. 166.4 per 100,000 pop, p < 0.05). A heterogeneous decrease in AM was registered between regions, ranging from −39% of Trento to − 17% of Molise. The analysis showed significant gender differences in AM, with females showing lower rates in both 2006/7 (144.5 vs. 306.3, p < 0.05) and 2018/9 (117.1 vs. 219.9, p < 0.05). Gender differences were also registered across regions, both overall and in terms of yearly % reduction. Conclusions While gender disparities in AM have reduced between 2006 and 2019 in Italy, the study shows that inequalities between regions have increased, thus underlying a worsening in the capacity of the Italian healthcare system to equally provide quality care to its population. We advocate the urgent need to reduce health disparities through a balanced regional development strategy. Key messages • Avoidable mortality is a key indicator for assessing quality and equity of healthcare. We have recorded significant gender and regional differences in this indicator between 2006 and 2019 in Italy. • Targeted interventions are needed to reduce gender and geographic disparities and to achieve the global goals of universalism and accessibility of health services, also in Italy.