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Dysfunction of the dopaminergic reward system has been implicated in the pathophysiology of several neuropsychiatric disorders. The endosomal network encompasses important processes related to neurotransmission in dopamine neurons, e.g., endocytosis, sorting, recycling and degradation of receptors. We investigated whether genetic variation influencing the endosomal sorting machinery, in particular cargo selection and membrane tubulation, may impact on the activation strength in key regions of the mesolimbic reward system, i.e. the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). To test our hypothesis, VTA and NAcc responses to conditioned reward stimuli were investigated using the 'desire-reason-dilemma' paradigm during functional magnetic resonance imaging in humans. Association of these neural responses with a set of genetic variants related to endosomal sorting processes (SNX1, SNX6, WASHC2C, WASHC3, WASHC4, DNAJC13) were tested in two independent cohorts (N = 182; N = 214). In the first cohort, the gene set was associated with both VTA and NAcc responses to conditioned reward stimuli [empirical P-values: R-VTA: 0.0036; R-NAcc: 0.0016; L-NAcc: 0.0094]. At the level of the gene set, the effect in the R-VTA could be replicated in the second cohort [empirical P-value: R-VTA: 0.0443]. For the NAcc, an additional exploratory analysis of a patient-only subcohort of the first cohort (N = 64) suggested that the gene set may express its effect in this brain region predominantly in patients. These findings provide first evidence that the endosomal sorting processes cargo selection and membrane tubulation may influence neural responses of the reward system to conditioned stimuli.