Background: An increased risk of cancer death has been demonstrated for patientsdiagnosed with acute coronary syndrome (ACS). We are investigating possiblegeographic risk disparities.Methods: This prospective study included 541 ACS patients who were admitted tohospitals and discharged alive in three provinces of Italy’s Veneto region. The patientswere classified as residing in urban or rural areas in each province.Results: With 3 exceptions, all patients completed the 22-year follow-up or were followeduntil death. Urban (46%) and rural (54%) residents shared most of their baselinedemographic and clinical characteristics. Pre-existing malignancy was noted in 15patients, whereas 106 patients developed cancer during the follow-up period, whichrepresented 6232 person-years. No difference in the cancer death risk was foundbetween the urban and rural areas or between southern and northern provinces(hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.7–1.7; p = 0.59 and HR 1.1; 95%CI 0.9–1.4; p = 0.29, respectively) according to the unadjusted Cox regression analysis.Geographic areas, however, showed a strong positive interaction, with risk increasingfrom the urban to rural areas from southern to northern provinces (HR 1.9; 95% CI 1.1–3.0; p = 0.01). The fully adjusted Cox regression and Fine-Gray competing risk regressionmodels provided similar results. Interestingly, these results persisted, and evenstrengthened, after exclusion of the 22 patients who developed malignancy andsurvived to the end of follow-up. We did not observe an urban/rural difference in nonneoplasticdeath risk or a significant interaction between the geographic areas.Conclusion: Our analysis reveals that the cancer death risk among unselected ACSpatients in Italy’s Veneto region significantly differs by geography. The northern rural areahas the highest risk. These results highlight the importance of implementing a preventivepolicy based on area-specific knowledge.