OBJECTIVES: Utilization of routine viral load (VL) and CD4 cell count coupled to clinical monitoring of HIV patients needs to be carefully deliberated in cost-effectiveness, especially for resource-limited countries. The review was aimed to evaluate and compare the cost-effectiveness of these strategies individually and in combination.  METHODS: A literature review was conducted for studies published in English from 2004 to 2014 on Pubmed, Web of Science, Ovid, Google Scholar, with keywords HIV, viral load, CD4, economic evaluation, and cost analysis. All underwent assignment of Levels of Evidence (LOE) by Oxford Center for Evidence-Based Medicine (CEBM), as well as Drummond scoring criteria.  RESULTS: Thirty English publications were identified, including 14 modeling studies, 7 randomized clinical trials (RCT's), and 5 cohort studies among others. A total of 24 were based on resource-limited settings such as Africa, Latin America, and Asia. Compared with CD4, VL alone had incremental cost-effectiveness ratios (ICER’s) ranging from $2520/LY to $3570/life year (LY); while that of CD4 alone compared to clinical monitoring was from $-13134/LY to $5768/quality-adjusted life year (QALY). The combination of CD4 and VL, which is recommended in real-life practice, compared to CD4 alone yielded ICER’s ranging from $3956/QALY to $16139/QALY. The cost-effectiveness of these strategies was affected by factors such as the reference threshold for ICER, costs and monitoring regimens of the strategies and antiretroviral treatment.  CONCLUSIONS: From the studies, it is critical to evaluate the cost-effectiveness of CD4 compared with VL contextually, with CD4 being more appropriate in resource-limited settings. VL is associated with improved benefit, however when used in combination with CD4, is usually not cost-effective. Compared with clinical monitoring alone CD4 usually produces greater cost-effectiveness.