The M184V substitution in HIV-1 RT develops rapidly following initiation of therapy with 3TC and confers high-level phenotypic resistance to this drug both in vitro and in vivo. Interestingly, the presence of M184V is also associated with alteration of several mechanisms relating to RT function that include decreased RT processivity, reduced nucleotide-dependent primer unblocking, increased fidelity, hypersensitization to other NRTIs, impaired viral fitness, and delayed appearance of mutations in RT that are responsible for resistance to thymidine analogues (i.e. thymidine-associated mutations or TAMs). Collectively, these factors might explain the residual antiviral effect and clinical benefit observed with continued use of 3TC in combination therapy regimens following the emergence of M184V. Indeed, the results of numerous controlled as well as observational clinical studies are suggestive of improved therapeutic outcome associated with continued usage of 3TC and maintenance of the M184V mutation. However, several of these trials did not possess adequate statistical power to resolve whether or not continued use of 3TC provided actual benefit, nor were they specifically designed to test the M184V benefit hypothesis in prospective fashion. There is a need for randomized clinical trials of this type in order to validate the potential benefit of maintenance of M184V and whether continued use of 3TC is the only means of attaining this objective.