On May 5, 2021, the Colorado Department of Public Health and Environment (CDPHE) identified the first five COVID-19 cases caused by the SARS-CoV-2 B.1.617.2 (Delta) variant in Mesa County in western Colorado (population 154,933, <3% of the state population). All five initial cases were associated with school settings. Through early June, Mesa County experienced a marked increase in the proportion of Delta variant cases identified through sequencing: the 7-day proportion of sequenced specimens identified as B.1.617.2 in Mesa County more than doubled, from 43% for the week ending May 1 to 88% for the week ending June 5. As of June 6, more than one half (51%) of sequenced B.1.617.2 specimens in Colorado were from Mesa County. CDPHE assessed data from surveillance, vaccination, laboratory, and hospital sources to describe the preliminary epidemiology of the Delta variant and calculate crude vaccine effectiveness (VE). Vaccination coverage in early May in Mesa County was lower (36% of eligible residents fully vaccinated) than that in the rest of the state (44%). Compared with that in all other Colorado counties, incidence, intensive care unit (ICU) admissions, and COVID-19 case fatality ratios were significantly higher in Mesa County during the analysis period, April 27-June 6, 2021. In addition, during the same time period, the proportion of COVID-19 cases in persons who were fully vaccinated (vaccine breakthrough cases) was significantly higher in Mesa County compared with that in all other Colorado counties. Estimated crude VE against reported symptomatic infection for a 2-week period ending June 5 was 78% (95% confidence interval [CI] = 71%-84%) for Mesa County and 89% (95% CI = 88%-91%) for other Colorado counties. Vaccination is a critical strategy for preventing infection, serious illness, and death from COVID-19. Enhanced mitigation strategies, including masking in indoor settings irrespective of vaccination status, should be considered in areas with substantial or high case rates.