To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Participants, 10-17 years of age, meeting The criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone ( = 86) or placebo ( = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32;  = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI -scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: NCT02075047 and NCT03768726.