© 2016 Vandewalle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The goal of this research was to establish a new and innovative framework for cost-effectiveness modeling of HIV-1 treatment, simultaneously considering both clinical and epidemiological outcomes. EPICE-HIV is a multi-paradigm model based on a within-host microsimulation model for the disease progression of HIV-1 infected individuals and an agentbased sexual contact network (SCN) model for the transmission of HIV-1 infection. It includes HIV-1 viral dynamics, CD4+ T cell infection rates, and pharmacokinetics/pharmacodynamics modeling. Disease progression of HIV-1 infected individuals is driven by the interdependent changes in CD4+ T cell count, changes in plasma HIV-1 RNA, accumulation of resistance mutations and adherence to treatment. The two parts of the model are joined through a per-sexual-act and viral load dependent probability of disease transmission in HIV-discordant couples. Internal validity of the disease progression part of the model is assessed and external validity is demonstrated in comparison to the outcomes observed in the STaR randomized controlled clinical trial. We found that overall adherence to treatment and the resulting pattern of treatment interruptions are key drivers of HIV-1 treatment outcomes. Our model, though largely independent of efficacy data from RCT, was accurate in producing 96-week outcomes, qualitatively and quantitatively comparable to the ones observed in the STaR trial. We demonstrate that multi-paradigm micro-simulation modeling is a promising tool to generate evidence about optimal policy strategies in HIV-1 treatment, including treatment efficacy, HIV-1 transmission, and cost-effectiveness analysis.