Objectives: We tested the hypothesis that neonatal cells are more sensitive to cardioplegia-induced cell swelling than more mature cells and spontaneous swelling in the absence of ischemia can be prevented by cardioplegia with a physiologic KCl product. Methods: Cell volumes of isolated ventricular myocytes from neonatal (3-5 days), intermediate (10-13 days), and adult (>6 weeks) rabbits were measured by digital video microscopy. After equilibration in 37°C physiologic solution, cells were suprafused with 37°C or 9°C St Thomas' Hospital solution (standard or low Cl-) or 9°C physiologic solution followed by reperfusion with 37°C physiologic solution. Results: Neonatal cells swelled 16.2% ± 1.8% (P < .01) in 37°C St Thomas' Hospital solution and recovered during reperfusion, whereas more mature cells maintained constant volume. In contrast, 9°C St Thomas' Hospital solution caused significant age-dependent swelling (neonatal, 16.8% ± 1.5%; intermediate, 8.6% ± 2.1%; adult, 5.6% ± 1.1%). In contrast to more mature cells, neonatal cells remained significantly edematous throughout reperfusion (8.1% ± 1.5%). Swelling was not due to hypothermia because 9°C physiologic solution did not affect volume. Lowering the KCl product of St Thomas' Hospital solution by partially replacing Cl- with an impermeant anion prevented cellular edema in all groups. Conclusion: In the absence of ischemia, neonatal cells were more sensitive to cardioplegia-induced cellular edema than more mature cells, and edema observed in all groups was avoided by decreasing the KCl product of St Thomas' Hospital solution to the physiologic range. Differences in cell volume regulation may explain the sensitivity of neonatal hearts to hyperkalemic cardioplegic arrest and suggest novel approaches to improving myocardial protection.