To evaluate the effect of volume of aspirates with different pHs on mortality associated with pulmonary aspiration, hydrochloric acid solutions were injected into the tracheas of 336 Sprague-Dawley rats. The rats were divided randomly into 33 groups, were observed for 96 hr after aspiration, and were not resuscitated. Deaths were divided into two groups: early, less than 30 min after aspiration, and late, greater than 4 hr after aspiration. Late deaths, accounting for 22% of all fatalities, occurred exclusively in animals aspirating solutions with a pH less than 2.5. These late deaths indicated progressive lung damage as opposed to acute cardiorespiratory failure, which early deaths suggested. Low volume pulmonary aspirates (0.3 ml/kg) with extremely low pH (1.0) resulted in a high mortality rate (90%). Conversely, higher volume pulmonary aspirates (1.0-2.0 ml/kg) with a higher pH (greater than or equal to 1.8) resulted in a low mortality rate (14%). These data demonstrate an important interaction between pH and volume of aspirates: even low volumes have a high mortality rate if pH is very low, whereas if gastric fluid is effectively buffered, then much higher volumes than previously thought can be tolerated. This suggests that the routine use of nonparticulate antacids may be indicated in patients at risk from aspiration of stomach contents and should not be withheld because of concern of increasing gastric volume.