The exact relationship between primary percutaneous coronary intervention (PCI) volume and mortality remains unclear. No data are available on how this relationship could be affected by time-to-presentation. The primary aim of this study was to evaluate the impact of hospital primary PCI volume on in-hospital mortality in ST-elevation myocardial infarction (STEMI) patients depending on time-to-presentation. The impact of primary PCI volume on in-hospital mortality was investigated in a prospective registry of the Lombardy region in Northern Italy, deriving data on mortality rates and number of primary PCIs from a cohort of 2,558 patients. We also explored this relationship at different times-to-presentation (≤90 min, >90 min-180 min, >180 min) and risk profiles assessed with the TIMI Risk Index. A strong inverse relationship was found between primary PCI hospital volume and risk-adjusted mortality (r = -0.9; P < 0.001). High primary PCI volumes best predicted the improvement of survival when the time-to-presentation was ≤90 min (area under the curve = 0.73, P < 0.0001). At this time, the best primary PCI threshold to provide benefit was >66 primary PCIs/year (OR = 0.21 [95% CI 0.10-0.47], P < 0.001) and those with high TIMI Risk Index achieved the greatest benefit (P < 0.001). At >90 min-180 min, the model was less significant (P = 0.02) with a higher threshold of procedures (>145 primary PCIs/year) required to provide benefits. The model was not predictive of survival for time-to-presentation >180 min (P = 0.30). The reduction of mortality of STEMI patients treated at high-volume primary PCI centers is time-dependent and affected by risk profile. The greatest benefit was observed in high-risk patients presenting within 90 min from symptoms onset.