OBJECTIVE: This evidence-based review evaluates the therapeutic interchangeability of levothyroxine between the original product Synthroid, and the two major generic brands Levoxyl and Levothroid, for use in hypothyroidism. METHODS: A literature search identified 8 bioequivalence trials comparing different formulations of levothyroxine tablets. Meta-analyses were conducted to compare average bioavailability using three pharmacokinetic measures (Total T4, Thyrotropin-stimulating Hormon [TSH], and Free Thyroxine Index [FTI]). These measures were also evaluated for differences in variability between treatment groups. RESULTS: The three formulations of Synthroid, Levoxyl, and Levothroid can be expected to produce similar average levels of circulating total T4 and TSH at steady state. Due to limited data, this statement does not extend to levels of free T4 nor free T3. Meta-analyses suggest that differences may exist in the variability of effect of levothyroxine products. Specifically, individual TSH levels in treated hypothyroid patients may span a wider range with some products than with others. This variability may be due to true individual differences in the variability of absorption of these products or to the use of outdated assay techniques (first generation radioimmunoassay) and short study durations that do not allow enough time for the patient to reach steady-state. CONCLUSION: Studies generally suggest that Synthroid, Levoxyl, and Levothroid are bioequivalent on average. However, population (between subject) variability may be different across products. Establishment of individual bioequivalence will require new, prospective studies of adequate treatment duration that use the most sensitive assay methodologies. Until such studies are undertaken, current treatment guidelines that recommend hypothyroid patients be reassessed 6 weeks after a change in brand or dose should remain in effect.