Skeletal muscle growth requires multiple steps to form large multinucleated muscle cells. Molecules that stimulate muscle growth may be therapeutic for muscle loss associated with aging, injury, or disease. However, few factors are known to increase muscle cell size. We demonstrate that prostaglandin F2alpha (PGF2alpha) as well as two analogues augment muscle cell size in vitro. This increased myotube size is not due to PGF2alpha-enhancing cell fusion that initially forms myotubes, but rather to PGF2alpha recruiting the fusion of cells with preexisting multinucleated cells. This growth is mediated through the PGF2alpha receptor (FP receptor). As the FP receptor can increase levels of intracellular calcium, the involvement of the calcium-regulated transcription factor nuclear factor of activated T cells (NFAT) in mediating PGF2alpha-enhanced cell growth was examined. We show that NFAT is activated by PGF2alpha, and the isoform NFATC2 is required for PGF2alpha-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling. Given this novel role for PGF2alpha in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.