PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (−/−) and their wild-type (+/+) and heterozygous (+/−) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas −/− mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/−, but not −/−, femurs and decreased the calcium content of −/−, but not +/+ or +/−, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/− vertebrae, but, in contrast, decreased trabecular bone in −/− vertebrae. Serum calcium levels in +/+ mice were greater than those in −/− mice, and PTH increased calcium in −/− mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in −/− mice. PTH also increased calvarial thickness in +/+ mice, but not −/− mice. The c-fos −/− mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in −/−, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.