Objective: The authors sought to test the efficacy of adjunctive ziprasidone in adults with nonpsychotic unipolar major depression experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram. Method: This was an 8-week, randomized, double-blind, parallel-group, placebo-controlled trial conducted at three academic medical centers. Participants were 139 outpatients with persistent symptoms of major depression after an 8-week open-label trial of escitalopram (phase 1), randomly assigned in a 1:1 ratio to receive adjunctive ziprasidone (escitalopram plus ziprasidone, N=71) or adjunctive placebo (escitalopram plus placebo, N=68), with 8 weekly follow-up assessments. The primary outcome measure was clinical response,definedas a reduction of at least50%in scoreonthe 17-item Hamilton Depression Rating Scale (HAM-D). The Hamilton Anxiety Rating scale (HAM-A) and Visual Analog Scale for Pain weredefined a priori as key secondaryoutcome measures. Results: Rates of clinical response (35.2% compared with 20.5%) and mean improvement in HAM-D total scores ( 6.4 [SD=6.4] compared with 3.3 [SD=6.2]) were significantly greater for the escitalopram plus ziprasidone group. Several secondary measures of antidepressant efficacy also favored adjunctive ziprasidone. The escitalopram plus ziprasidone group also showed significantly greater improvement on HAM-A score but not on Visual Analog Scale for Pain score. Ten (14%) patients in the escitalopram plus ziprasidone group discontinued treatment because of intolerance, compared with none in the escitalopram plus placebo group. Conclusions: Ziprasidone as an adjunct to escitalopram demonstrated antidepressant efficacy in adult patients with major depressive disorder experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram.