Objective Ziprasidone may improve cognition in schizophrenia; however, this could be related to clinical symptom improvement, reflecting “pseudospecificity”. We tested the hypothesis that ziprasidone improves cognition in the absence of clinical improvement. Methods We conducted a 12-week, open-label study of ziprasidone in 10 schizophrenia patients who met non-response criteria (<20% reduction in BPRS scores over 12 weeks). We conducted comprehensive cognitive testing and assessed change from baseline to end of study. Results We detected significant improvement on three measures of episodic memory (p <0.01) in these clinically non-responsive patients. Trend-level improvements were noted on tests involving processing speed and executive function. Conclusions These data suggest that ziprasidone has cognitive benefits unrelated to an influence on other disease parameters.