ObjectiveThe aim of this paper was to review and compare HIV vaccine cost-effectiveness analyses and describe the effects of uncertainty in model, methodology, and parameterization.MethodsWe systematically searched MEDLINE (1985 through May 2016), EMBASE, the Tufts Cost-Effectiveness Analysis (CEA) Registry, and the reference lists of articles following Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligibility criteria included peer-reviewed manuscripts with economic models estimating the cost-effectiveness of preventive HIV vaccines. Two reviewers independently assessed study quality and extracted data on model assumptions, characteristics, input parameters, and outcomes.ResultsThe search yielded 71 studies, 11 of which met the inclusion criteria. Populations included low-income (n = 7), middle-income (n = 4), and high-income countries (n = 2). Model structure varied, including decision tree (n = 1), Markov (n = 5), compartmental (n = 4), and microsimulation (n = 1). Most studies measured outcomes in quality-adjusted life-years (QALYs) gained (n = 6), whereas others used unadjusted (n = 3) or disability-adjusted life-years (n = 2). The range of HIV vaccine costs were $US1.54–75 in low-income countries, $US55–100 in middle-income countries, and $US500–1000 in the USA. Base-case incremental cost-effectiveness ratios (ICERs) ranged from dominant (cost offsetting) to $US91,000 per QALY gained.ConclusionMost models predicted HIV vaccines would be cost-effective. Model assumptions about vaccine price, HIV treatment costs, epidemic context, and willingness to pay influenced results more consistently than did assumptions on HIV transmission dynamics.Electronic supplementary materialThe online version of this article (doi:10.1007/s41669-016-0009-9) contains supplementary material, which is available to authorized users.