PURPOSE: Multiresistant (MR) bacteria neonatal sepsis has been progressively increasing worldwide, raising the risk of death. This study aimed to evaluate the incidence of late-onset neonatal sepsis (LOS) and the incidence of MR agents in very low birth weight (VLBW) infants in a Brazilian tertiary neonatal unit over 15 years. METHODS: This was a retrospective temporal trend study. All VLBW infants admitted from 2006 to 2020 diagnosed with LOS caused by Staphylococcus aureus, Enterococcus spp or Gram-negative bacilli were eligible. RESULTS: During the period, 259/1,575 (16.4%) VLBW infants had confirmed LOS, corresponding to 311 episodes of sepsis, 114 of them by agents of interest. There were 20 episodes of MR bacteria LOS (6.4% of the total confirmed LOS), corresponding to 17.5% of the cases of LOS by the studied agents, and to an incidence of 12.7/1,000 admitted VLBW infants. There was a significant trend towards a reduction in the rate of confirmed LOS (P = 0.010), while the trend of incidence of MR agents' sepsis remained stable (1.3 episodes per year - range 0-4/year). The MR incidence corresponded to 18.4% for S. aureus and 19% for Gram-negative bacilli strains. There were no cases of MR Enterococcus or carbapenemase-producing organisms. The rate of sepsis-related in-hospital death was not statistically different between the MR and non-resistant sepsis groups (15.0 versus 19.1%, P = 1,000). CONCLUSION: The incidence of confirmed LOS in VLBW infants has shown a downward trend, while the rate of LOS due to MR bacteria has remained low and stable over 15 years.