Thromboembolic and bleeding complications are common after asphyxia. We studied the temporal effects of different oxygen concentrations used in resuscitating hypoxic newborn piglets on platelet aggregatory function. Alveolar normocapnic hypoxia (fractional inspired oxygen concentration = 0.15) was induced in piglets (1-4 d, 1.7-2.5 kg) for 2 h, followed by reoxygenation with 18%, 21%, or 100% oxygen for 1 h and then 21% for 2 h (n = 8-9 per group). Control piglets underwent surgery with no hypoxia-reoxygenation (n = 5). Platelet counts and collagen-stimulated (2-10 microg/mL) whole blood aggregation were studied at normoxic baseline and at 3 h, 2 d, and 4 d of recovery. Platelet activation markers including plasma thromboxane B2 and matrix metalloproteinase 2 and 9 levels were measured. At 2 h hypoxia (mean PaO2 30-35 mmHg), all piglets were hypotensive and acidotic (mean pH 7.19-7.24). In 100% reoxygenation piglets, the concentration-response curves of collagen-stimulated platelet aggregation were significantly shifted upward at 3 h and 2 d of recovery with no differences in the collagen concentration required to induce 50% of maximum aggregation, and this normalized to baseline on 4 d. In the 18% and 21% reoxygenated groups, there were no changes in platelet aggregation during the experiment. Platelet counts were not different between groups and over time. Hypoxic-reoxygenated piglets had increased plasma thromboxane B2 (100% group) and matrix metalloproteinase-2 levels (21% and 100% groups) (versus respective baseline, P < 0.05), with no difference between experimental groups. These findings suggest transient platelet activation in hypoxic newborn piglets resuscitated with 100% but not with 18% and 21% oxygen, of which the clinical significance requires further investigation.