Background: Treating vessels with a very small reference vessel diameter (RVD) in coronary artery disease is challenging. Objective: Long-term evaluation of new-generation drug-eluting stents (DESs) for the treatment of coronary lesions with different RVDs. Methods: From April 2009 to March 2019, 780 patients who underwent single coronary stenting were divided into 2.25 (very small), 2.5-3.0 (small), and 3.5 mm (large) DES groups after 1:2:2 propensity score matching. The primary endpoint was target lesion failure (TLF), and the secondary endpoints were major adverse cardiac events (MACEs) and stent thrombosis (ST). Results: During 3 years after new-generation DES implantation, TLF and MACE rates were significantly lower in the very small DES group. The risk of TLF was significantly lower in the very small DES group compared to the small DES group [very small vs. small: TLF, adjusted hazard ratio (HR) = 0.282, p = 0.040]. The risks of MACEs and all-cause mortality were significantly lower in the very small DES group compared to the small DES group (very small vs. small: MACEs, adjusted HR = 0.215, p = 0.001; all-cause mortality, adjusted HR = 0.181, p = 0.005). The cumulative incidence rates of TLF-free (log-rank test p = 0.001) and MACE-free (log-rank test p < 0.001) survival were significantly different among the groups, and the very small DES group had a high event-free survival rate. No cases of ST occurred in any group. Conclusions: Our results indicate that the use of new-generation DESs for treating coronary lesions in very small vessels is safe and effective.