Molybdenum disulfide (MoS2) exhibits exceptional mechanical and wear properties combined with thermal stability, which makes it an outstanding solid lubricant. While numerous studies have reported on the tribological behavior of few-layer pristine MoS2, little attention has been given to the impact of defects, such as sulfur vacancies, which are inevitable during large-scale fabrications. Understanding the factors that affect friction at the atomic level is essential for the design and optimization of high-performance materials. Here, we present a systematic study of the tribology of one- and two-layer MoS2 nanosheets, with controllably introduced atomic vacancies, performed by atomic force microscopy. We find that the friction coefficient of mono- and bilayer MoS2 suffers more than a 3-fold increase from the as-prepared layer (with an initial defect density of 1 × 1012 cm–2) to those with an induced atomic defect density of 1.2 × 1013 cm–2. Comparison of the results reported here with analogous results in graphene shows that MoS2 presents an attractive high resilience of the friction coefficient to monatomic defect generation in the atomic defect density range typically obtained by scalable techniques. [Full article]