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Background: Sleep deprivation (SD) is commonplace in modern society and there are large individual differences in the vulnerability to SD. We aim to identify the structural network differences based on diffusion tensor imaging (DTI) that contribute to the individual different vulnerability to SD. Methods: The number of psychomotor vigilance task (PVT) lapses was used to classify 49 healthy subjects on the basis of whether they were vulnerable or resistant to SD. DTI and graph theory approaches were used to investigate the topologic organization differences of the brain structural connectome between SD‐vulnerable and ‐resistant individuals. We measured the level of global efficiency and clustering in rich club and non‐rich club organizations. Results: We demonstrated that participants vulnerable to SD had less global efficiency, network strength, and local efficiency but longer shortest path length compared with participants resistant to SD. Lower efficiency was mainly distributed in the right insula, bilateral thalamus, bilateral frontal, temporal, and temporal lobes. Furthermore, a disrupted subnetwork was observed that consisted of widespread connections. Moreover, the vulnerable group showed significantly decreased strength of the rich club compared with the resistant group. The strength of rich club connectivity was found to be correlated negatively with PVT performance (r = −0.395, p = 0.005). We further tested the reliability of the results. Conclusion: The findings revealed that individual differences in resistance to SD are related to disrupted topologic efficiency connectome pattern, and our study may provide potential connectome‐based biomarkers for the early detection of the vulnerable degree to SD. [ABSTRACT FROM AUTHOR]