Background: Residual viraemia is a major obstacle to HIV-1 eradication in subjects receiving HAART. The intensification with raltegravir could impact latent reservoirs and might lead to a reduction of plasma HIV-1 viraemia (viral load [VL]), complementary DNA intermediates and immune activation. Methods: This was a prospective, open-label, randomized study comprising 69 individuals on suppressive HAART randomly assigned 2:1 to add raltegravir during 48 weeks. Results: Total and integrated HIV-1 DNA, and ultrasensitive VL remained stable despite intensification. There was a significant increase in episomal HIV DNA at weeks 2-4 in the raltegravir group returning to baseline levels at week 48. Median CD4 + T-cell counts increased 124 and 80 cells/μl in the intensified and control groups after 48 weeks (P=0.005 and P=0.027, respectively), without significant differences between groups. No major changes were observed in activation of CD4 + T-cells. Conversely, raltegravir intensification significantly reduced activation of CD8 + T-cells at week 48 (HLA-DR +CD38 +, P=0.005), especially in the memory compartment (CD38 + of CD8 +CD45RO +, P<0.0001). Linear mix models also depicted a larger decrease in CD8 + T-cell activation in the intensification group (P=0.036 and P=0.010, respectively). Raltegravir intensification was not associated to any particular adverse event. Conclusions: Intensification of HAART with raltegravir during 48 weeks was safe and associated with a significant decrease in CD8 + T-cell activation, and a transient increase of episomal HIV-1 DNA. However, raltegravir did not significantly contribute to changes in CD4 + T-cell counts, ultrasensitive VL, and total and integrated HIV-1 DNA. These findings suggest that raltegravir impacts residual HIV-1 replication and support new strategies to impair HIV-1 persistence. © 2012 International Medical Press.