This study aimed to estimate thecost-effectiveness and returns on investments of HIVprevention programs implemented during 2006-2010 and toidentify the optimal allocation of resources acrosscombinations of programs for an effective HIV preventionresponse to inform the prioritization of funding and healthresources in Vietnam. The spending-outcome relationships andan epidemiological model were used to compare observedconditions with counterfactual scenarios of reduced or noprograms to calculate the cost-effectiveness and estimatehealthcare costs saved and thus the return on investment.Model simulations of epidemic projections over manycombinations of possible resource allocations were used toidentify optimal allocations for reducing new infectionsover the next HIV budget period.