The present 16-week double-blind, randomized, placebo-controlled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms (Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale "Negative" (P = 0.006, mean change [SD] in active group vs placebo, -2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and "General Psychopathology" (P = 0.009, mean change [SD] in active group vs placebo, -5.3 [3.8] vs -0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P < 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs -0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within-group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002). Ziprasidone added to clozapine was effective on negative and cognitive symptoms, although it may be proposed as a helpful treatment in schizophrenia, mainly for those patients who partially respond to clozapine monotherapy.