CONTEXT: In some patients symptoms of hypothyroidism persist despite therapy with T(4). OBJECTIVE: The objective of the study was to compare the effectiveness of T(4)-T(3) combination vs. T(4) monotherapy for the treatment of clinical hypothyroidism in adults. DATA SOURCES: PubMed, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched in September 2005. References of all included trials were scanned for additional studies. We put no restrictions on language, year of publication, or publication status. STUDY SELECTION: All randomized trials that compared the effectiveness of T(4)-T(3) combination vs. T(4) monotherapy for the treatment of clinical hypothyroidism in adults were included. DATA EXTRACTION: The data were extracted by two independent reviewers. DATA SYNTHESIS: We included 11 studies, in which 1216 patients were randomized. No difference was found in the effectiveness of combination vs. monotherapy in any of the following symptoms: bodily pain [standardized mean difference (SMD) 0.00, 95% confidence interval (CI) -0.34, 0.35], depression (SMD 0.07, 95% CI -0.20, 0.34), anxiety (SMD 0.00, 95% CI -0.12, 0.11), fatigue (SMD -0.12, 95% CI -0.33, 0.09), quality of life (SMD 0.03, 95% CI -0.09, 0.15), body weight, total serum cholesterol, triglyceride levels, low-density lipoprotein, and high-density lipoprotein. Adverse events did not differ between regimens. CONCLUSIONS: T(4) monotherapy should remain the treatment of choice for clinical hypothyroidism.