Whether and how sleep loss affects executive functioning are still under debate. In this study, we examined the role of individual differences in determining the levels of working memory (WM) efficiency and proactive interference (PI) after sleep deprivation. Fifty-two participants performed a test battery included a modified Sternberg task and the Jonides’ 2-back task under two sleep conditions: baseline (BL, a night of regular sleep), and total sleep deprivation (SD, 24 h of wakefulness). In general, we replicated Tucker and colleagues’ (2010) results. However, when we divided the subjects into two groups according to WM efficiency after SD, participants that showed a greater efficiency were more susceptible to PI, while those with lower WM efficiency showed a level of resistance to PI similar to BL. These results indicate that resistance to PI after SD is dependent on WM efficiency, highlighting the importance of individual differences in sleep deprivation studies.