<p>Fine particulate matter (PM_2.5) is a major environmental risk factor associated with increased mortality from cardiovascular and respiratory diseases worldwide. This study examined the short-term association between daily PM_2.5 exposure and cause-specific mortality in Mashhad, a large metropolitan city in northeastern Iran, over the period from March 2019 to March 2024. Daily concentrations of PM_2.5 were obtained from a city-wide air quality monitoring network, and mortality data for ischemic heart disease, stroke, chronic obstructive pulmonary disease, acute lower respiratory infection, asthma, and lung cancer were collected from official health records. A time-series analysis was conducted using generalized additive models with a quasi-Poisson distribution to estimate relative risks and 95% confidence intervals associated with a 10&#xa0;µg/m³ increase in PM_2.5 concentrations. Both single-day lag effects (0–5 days) and cumulative lag effects were evaluated, while accounting for temporal trends and meteorological variables. The results showed that short-term increases in PM_2.5 concentrations were significantly associated with higher mortality from ischemic heart disease, stroke, chronic obstructive pulmonary disease, and acute lower respiratory infection, with the strongest effects generally observed at lag days 4–5 and cumulative lag periods. No statistically significant short-term associations were detected for asthma or lung cancer mortality. In addition, PM_2.5 concentrations consistently exceeded the World Health Organization guideline during most of the study period, indicating sustained population exposure to elevated air pollution levels. These findings provide evidence that short-term exposure to PM_2.5 contributes to increased cause-specific mortality in an urban Middle Eastern setting and highlight the public health importance of effective air pollution control strategies to reduce preventable deaths.</p>