While injectable fillers for facial-volume augmentation have been extensively marketed, there are few published reports comparing the clinical efficacy and cost-effectiveness of multiple injectable agents for soft-tissue augmentation in the face. We present our experience in 976 patients with the use of 4 common injectable agents: autologous fat, Hylaform, Restylane, and Radiesse. We analyzed the injection characteristics of each filler, including injection volume, complication rate, revision rate, and longevity, across 3 commonly treated anatomic regions: the nasolabial fold, glabella, and lips. We subsequently performed a detailed cost-effectiveness analysis of each filler in each anatomic region. Our results demonstrate that autologous fat transplantation is ideally suited for the treatment of the nasolabial fold and glabella, particularly in combination with other procedures. Fat grafting to the lips is limited to use as an adjunct to other facial surgery due to the prolonged recovery time required. We prefer Radiesse for the isolated treatment of the nasolabial folds and glabella. However, Radiesse is not recommended in the lips due to the increased incidence of complications. Last, the hyaluronic fillers Restylane and Hylaform have an excellent safety profile and are our first choice for isolated lip augmentation procedures.