OBJECTIVES: ENF blocks fusion of HIV-1 to host cells. Phase III trials, TORO 1 & 2, demonstrated that ENF in combination with optimized backgrounds (OB) provided additional viral suppression and immune reconstitution compared to OB alone in antiretroviral experienced patients. We constructed two interactive models to evaluate cost-effectiveness and budgetary impact of ENF. METHODS: Treatment effects on time to virological failure, 24-week change from baseline in HIV-1 viral load and CD4+ cell count were from clinical findings. Time to immunological failure (IF), AIDS-defining event (ADE), and death were estimated by linking data mathematically to published disease-progression models. Direct costs were calculated from published estimates. The incremental cost per quality-adjusted life year (QALY) gained (ICER) was estimated using the societal perspective. The BIA estimated financial impact of adding ENF to formularies across total health care costs versus pharmacy costs only. Total costs of treating eligible HIV population for four years and cost per member per month (PMPM) were calculated for a hypothetical health plan. Most input variables can be changed to reflect plan characteristics and patient experiences. RESULTS: Treatment effects of ENF+OB vs. OB alone indicate a decline in the annual rate of IF from 73% on OB to 37% on ENF+OB. The combined treatment effects are predicted to increase mean survival by 1.6 years (1.3 QALYs). The ICER of ENF+OB is estimated to be $36,238/QALY. BIA showed added costs of $5,074,472 ($1.69 PMPM) for ENF treatment in the first year, and $1,222,279 ($0.28 PMPM) annually in subsequent years. Sensitivity analyses showed that ADE risk as a function of CD4, time to IF, and baseline CD4+ cell count most affected cost-effectiveness estimates. CONCLUSIONS: Combining drug plan benefits with CEA enables a more comprehensive understanding of the economic implications of ENF. The transparent and interactive models allow Health care decision-makers to understand and utilize them to estimate ENF's cost-effectiveness and budgetary impact easily.