This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H3 receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7weeks (4weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=−0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=−0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.