We read with interest the impressive meta-analysis by Davis et al¹ of the efficacy of second-generation antipsychotics (SGAs) published in the ARCHIVES but were concerned about its inadequate consideration of some important methodologic limitations that may have significantly detracted from the veracity of their conclusions. There are approximately 50 different antipsychotic medications available in the world; of the 20 currently available in the United States, 6 (clozapine, risperidone, olanzapine, quetiapine fumarate, ziprasidone hydrochloride, and aripiprazole) are labeled SGAs. Perhaps because of their presumed broader spectrum of efficacy and better motor adverse-effect profile, SGAs collectively constitute more than 90% of all antipsychotic prescriptions in the United States at this time. Despite the wide popularity of these medications and their rapid adoption in general clinical practice, there are limited data on how they compare with each other with regard to their overall efficacy. In an effort to address this issue, Davis et al¹ performed a meta-analysis of 124 randomized controlled trials (published and unpublished) with efficacy data on 1 of 10 SGAs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, remoxipride, risperidone, sertindole, ziprasidone, and zotepine) vs a first-generation antipsychotic (FGA). Based on their analysis, they concluded that there are 2 groups of SGAs: group 1 (comprising amisulpride, clozapine, olanzapine, and risperidone) is more efficacious than FGAs and group 2 (comprising the other 6) is not differently efficacious than FGAs. Furthermore, in an additional analysis of 18 trials comparing SGAs among each other, they found no evidence for differential efficacy among amisulpride, clozapine, olanzapine, and risperidone. Finally, they found no support for the contention that the observed greater efficacy of SGAs over FGAs in part is explained by the use of high doses of a comparator FGA (>12 mg of haloperidol per day). While the exhaustive efforts of Davis et al merit praise, key methodologic limitations in their report warrant further discussion.