Differentiating bipolar disorders (BD) from unipolar depression (UD) remains a major clinical challenge. The identification of neurobiological markers may help to differentiate these disorders, particularly during depressive episodes. This cross-sectional study, including 33 patients with UD, 33 patients with BD, and 34 healthy controls, is one of the first to directly compare UD and BD with respect to reward processing. A card-guessing paradigm was employed and brain activity associated with reward processing was investigated by means of fMRI. A 3 (group) × 2 (condition: reward>control, loss>control) ANOVA was conducted using the nucleus accumbens (NAcc) as ROI. Furthermore, a whole-brain approach was applied. A functional connectivity analysis was performed to characterize diagnosis-related alterations in the functional coupling between the NAcc and other brain areas. The ANOVA revealed higher activity for healthy controls (HCs) than for BD and UD in the NAcc during reward processing. Moreover, UD showed a higher functional connectivity between the NAcc and the VTA than HC. The patients groups could be differentiated in that BD showed a decreased activation, in the reward condition, of the NAcc, caudate nucleus, thalamus, putamen, insula, and prefrontal areas compared with UD. These results may help to refine the understanding of neural correlates of reward processing in both disorders, and to understand the neural underpinnings of anhedonia, a core symptom of depressive episodes.