Objective: To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. Methods: This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebocontrolled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. Results: Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. Conclusions: In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.