Controversy persists over the relative tolerance of the immature myocardium to global ischemia. Thus, we evaluated the physiologic effects of 30, 60, and 180 minutes of global ischemia in an isolated, isovolumic rabbit heart model, at 3 different ages: newborns (less than 1 week of age) (n = 36), juveniles (4 to 6 weeks old) (n = 36), and adults (5 to 7 months old) (n = 36). Following 30 and 60 minutes of ischemia, respectively, adults recovered 87 ± 4% (mean ± SEM) and 90 ± 7% of baseline systolic function, and juveniles recovered 91 ± 10% and 85 ± 8%. In contrast, newborns recovered only 27 ± 6% and 28 ± 4% of baseline systolic function (p<0.05 compared to adults and juveniles). During ischemia, newborn hearts became stiff more rapidly, reaching 361 ± 46% of baseline stiffness by 60 minutes, whereas adults and juveniles were at 122 ± 33% and 92 ± 18% of baseline stiffness (p<0.05 newborns compared to adults and juveniles). With reperfusion after 60 minutes of ischemia, the work efficiency of the newborn heart deteriorated to 39 ± 7% of baseline, compared with 95 ± 7% and 91 ± 7% of baseline efficiency in the adult and juvenile hearts (p<0.05, newborns compared to adults and juveniles). The ratio of tissue wet-to-dry weights were similar in all age groups after ischemia. However, tissue pH was significantly higher in newborns during ischemia (6.54 ± 0.06, 6.69 ± 0.07, and 6.85 ± 0.09 in adults, juveniles, and newborns, after 60 minutes of ischemia) (p<0.05 newborns versus adults). We conclude that the newborn rabbit hearts are more susceptible to ischemic injury than the juvenile and adult hearts. (Circulation Research 1987;61:609-615)