The objective of this substudy was to examine the effect of desvenlafaxine 50 mg/day compared with placebo on cognitive function in employed outpatients with major depressive disorder. A total of 11/55 (20%) study sites in a 12-week, randomized, double-blind, placebo-controlled trial administered cognitive assessments in memory, attention, and executive functioning domains using the cognitive drug research system. Changes from baseline were subjected to analysis of covariance with baseline levels as covariates, using last observation carried forward data.A significant improvement with desvenlafaxine 50 mg/day(n=52) compared with placebo (n=29) was observed on the quality of working memory composite measure (0.081 units (0.005, 0.156); P=0.0365) at last observation carried forward. Improvement from baseline on the speed of working memory composite was significant for desvenlafaxine (−226.6 msec (−316.7, −136.4); P<0.0001) and for placebo (−133.3 msec (−257.2, −9.4); P=0.0354); however, the treatment effect was not significant. No significant differences between groups were observed on composite measures for attention. Treatment of depression with desvenlafaxine 50 mg/day may improve aspects of cognitive functioning, including working memory.