In the urban area of Santiago de Cuba, a total of 19,031 dengue cases were diagnosed between January 2015 and March 2020. Two epidemic periods (one during the PI and one during the PR period) were identified within the endemic channel at the municipal level. The DI reached a peak of approximately 700 cases per 100,000 inhabitants in November 2015. The analysis based on routine data showed that during PR, the house index was lower in the intervention area compared to the control (2018 relative risk, RR=0.50, 95% confidence interval (CI) [0.42,0.59]), as was the case for dengue incidence (in 2018, RR=0.41, 95% CI [0.30,0.54], and in 2019, RR=0.76, 95% CI [0.65,0.88]). The controlled interrupted time series revealed an immediate decrease in the house index (72.8%, 95% CI: [51.1, 84.9]) and dengue incidence (76.9%, 95% CI: [20.7, 93.3]) at the start of the intervention. Difference-in-differences analysis revealed a significant effect during nonepidemic periods (incidence rate ratio, IRR = 0.40, 95% CI: [0.17, 0.92]) but not during epidemics (IRR = 0.68, 95% CI: [0.26, 1.81]). The intervention also reduced the contribution of the area to the dengue caseload incidence at the municipal level, decreasing from 67.1% at the start of the intervention to 51.3% in 2019. Given the growing focus on reconsidering dengue control measures with an emphasis on spatial transmission variability, the positive impact on vector density and dengue incidence of a multicomponent vector control strategy targeting transmission hotspots is encouraging but needs to be further confirmed by larger trials.