This chapter summarizes the features of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial that are relevant to interpretation of extrapyramidal side effects (EPS) findings. CATIE was designed to address the overall effectiveness of second-generation antipsychotic (SGA) versus a mid-potency first-generation antipsychotic drugs (FGA), perphenazine, based on treatment discontinuation. Using measures of dystonia, Parkinsonism, akathisia, and tardive dyskinesia (TD), the analysis of incidence rates and continuous measures from CATIE shows no substantial or statistically significant differences between modest doses of the intermediate potency FGA perphenazine and four SGAs in patients with chronic schizophrenia requiring maintenance antipsychotic treatment. The conclusion that must be drawn from the CATIE study is that there were no significant differences in primary outcome measures of acute EPS and TD overall, while at the same time perphenazine was shown to be not different in overall effectiveness compared with olanzapine, risperidone, quetiapine, and ziprasidone.