We performed a multisite study to evaluate demographic and clinical conditions as potential modifiers of the particulate matter (PM)-mortality association. We selected 228,619 natural deaths of elderly persons (ages ≥65 years) that occurred in 12 Italian cities during the period 2006-2010. Individual data on causes of death, age, sex, location of death, and preexisting chronic and acute conditions from the previous 5 years' hospitalizations were collected. City-specific conditional logistic regression models were applied within the case-crossover "time-stratified" framework, followed by random-effects meta-analysis. Particulate matter less than or equal to 2.5 µm in aerodynamic diameter (PM2.5) and particulate matter less than or equal to 10 µm in aerodynamic diameter (PM10) were positively associated with natural mortality (1.05% and 0.74% increases in mortality risk for increments of 10 µg/m3 and 14.4 µg/m3, respectively), with greater effects being seen among older people, those dying out-of-hospital or during the warm season, and those affected by 2 or more chronic diseases. Limited associations were found among persons with no previous hospital admissions. Diabetes (1.98%, 95% confidence interval (CI): 0.54, 3.44) and cardiac arrhythmia (1.65%, 95% CI: 0.37, 2.95) increased risk of PM2.5-related mortality, while heart conduction disorders increased risk of mortality related to both PM2.5 (4.22%, 95% CI: 0.15, 8.46) and PM10 (4.19%, 95% CI: 0.38, 8.14). Among acute conditions, recent hospital discharge for heart failure modified the PM10-mortality association. The study found increases in natural mortality from PM exposure among people with chronic morbidity; diabetes and cardiac disorders were the main susceptibility factors.