OBJECTIVE To provide an overview of the economic aspects of needlestick and sharps injury (NSI) management among healthcare personnel (HCP) within a Health Technology Assessment project to evaluate the impact of safety-engineered devices on health care METHODS A systematic review of economic analyses related to NSIs was performed in accordance with the PRISMA statement and by searching PubMed and Scopus databases (January 1997-February 2015). Mean costs were stratified by study approach (modeling or data driven) and type of cost (direct or indirect). Costs were evaluated using the CDC operative definition and converted to 2015 International US dollars (Int$). RESULTS A total of 14 studies were retrieved: 8 data-driven studies and 6 modeling studies. Among them, 11 studies provided direct and indirect costs and 3 studies provided only direct costs. The median of the means for aggregate (direct + indirect) costs was Int$747 (range, Int$199-Int$1,691). The medians of the means for disaggregated costs were Int$425 (range, Int$48-Int$1,516) for direct costs (9 studies) and Int$322 (range, Int$152-Int$413) for indirect costs (6 studies). When compared with data-driven studies, modeling studies had higher disaggregated and aggregated costs, but data-driven studies showed greater variability. Indirect costs were consistent between studies, mostly referring to lost productivity, while direct costs varied widely within and between studies according to source infectivity, HCP susceptibility, and post-exposure diagnostic and prophylactic protocols. Costs of treating infections were not included, and intangible costs could equal those associated with NSI medical evaluations. CONCLUSIONS NSIs generate significant direct, indirect, potential, and intangible costs, possibly increasing over time. Economic efforts directed at preventing occupational exposures and infections, including provision of safety-engineered devices, may be offset by the savings from a lower incidence of NSIs. Infect Control Hosp Epidemiol 2016;37:635-646.