The pulmonary response to hyperoxia is highly variable, depending on such seemingly disparate biologic factors as gestational age, sex, hormonal milieu, and nutritional status. Descriptively, the magnitude and direction of these biologic differences in response to hyperoxia correlate with the triglyceride content of developing fetal rat lung fibroblasts (FRLFs). Mechanistically, these same factors affect the triglyceride content of FRLFs, e.g. d 21 FRLFs contain more triglyceride than d 18 FRLFs; female FRLFs contain more triglyceride than male FRLFs (d 20); dexamethasone increases FRLF triglyceride content, dihydrotestosterone decreases it; nutritionally, exposure of FRLFs to graded amounts of serum triglyceride (0%, 2%, 10%, 20%) results in increased intracellular FRLF triglyceride content. To test the hypothesis that these biologic differences in intracellular triglyceride content may account for differences in the cytoprotection of lung fibroblasts against oxidant injury, fibroblast cultures representing each of these biologic groups were challenged with graded doses of the reactive oxygen species hydrogen peroxide (0.1-1.0 mM for 5 min). The number of surviving cells and their antioxidant status, as measured by lipid peroxidation and glutathione content of the surviving cells, were determined. We found that in response to hydrogen peroxide 1) d 21 FRLFs were more resistant than d 18 FRLFs; 2) female FRLFs were more resistant than male FRLFs; 3) dexamethasone-treated FRLFs were more resistant than dihydrotestosterone-treated fibroblasts; 4) fibroblasts fed increasing amounts of serum triglycerides were increasingly resistant to hydrogen peroxide; 5) cell survival in different serum triglyceride- and hormone-treated groups was not related to the antioxidant status as measured by glutathione content. These data are consistent with the hypothesized role of FRLF triglycerides as antioxidants.