Reward deficits and associated striatal circuitry disturbances have been implicated in the onset and progression of major depressive disorder (MDD). However, no studies have been conducted to investigate how the striatal circuitry changes during standard antidepressant, which is important for development of novel and targeted treatments for MDD. We examined the seed-to-whole-brain functional connectivity (FC) for six striatal subregions based on resting-state fMRI data of 23 MDD patients before and after 8-week duloxetine, a serotonin, and noradrenaline reuptake inhibitor. Twenty-three healthy controls (HCs) were also scanned twice with an 8-week interval. After the analysis of covariance, we observed significant group-by-time interaction on FC of the dorsal caudate (DC), ventral striatum (VS), and putamen seeds. Post hoc analyses revealed that the FC between several right striatal seeds and left superior frontal gyrus (SFG), between right DC and left precuneus, between right superior VS and left inferior parietal lobe, were significantly higher in MDD patients compared to HCs at baseline and were reduced after treatment. Conversely, the FC between right inferior VS and left cerebellum was lower in MDD patients and was increased after treatment. Patients with larger reduction in right superior VS—left SFG FC exhibited larger alleviation of rumination. These findings suggest that duloxetine modulates the striatal FC with dorsolateral prefrontal cortex, posterior default mode network, and cerebellum, and partly, these changes underlie symptomatic improvement. This study adds to our understanding of antidepressant mechanism and future therapeutic development might benefit from considering these striatal circuitry as potential targets. ? 2019 Wiley Periodicals, Inc.