Objective. To assess the effects of hospital volume of very low-birthweight (VLBW) infants on in-hospital mortality of VLBW and very preterm birth (VPB) infants in South America. Data Sources/Study Setting. Birth-registry data for infants born in 1982–2008 at VLBWor very preterm in 66 hospitals in Argentina, Brazil, and Chile. Design. Regression analyses that adjust for several individual-level demographic, socioeconomic, and health factors; hospital-level characteristics; and country-fixed effects are employed. Data Collection/Extraction Methods. Physicians interviewed mothers before hospital discharge and abstracted hospital medical records using similar methods at all hospitals. Principal Findings. Volume has significant nonlinear beneficial effects on VLBW and VPB in-hospital survival. The largest survival benefits––more than 80 percent decrease in mortality rates––are with volume increases from low to medium or medium-high levels (from 25 to 72 infants annually) with significantly lower incremental benefits thereafter. The cumulative volume effects are maximized at the 121–144 annual VLBW infant range––about 90 percent decrease in mortality rates compared to <25 VLBW infants annually. Conclusions. Increasing the access of pregnancies at-risk of VLBW and VPB to medium- or high-volume hospitals up to 144 VLBW infants per year may substantially improve in-hospital infant survival in the study countries.