Background: HIV DNA mirrors the number of infected cells and the size of the HIV viral reservoir. The aim of this study was to evaluate the effect of pre-cART HIV DNA levels as a predictive marker of immune reconstitution and on the post-cART CD4 counts trends. Methods: HIV DNA was isolated from PBMCs and quantified by real-time PCR. Immune reconstitution was assessed up to four years. Piecewise-linear mixed models were used to describe CD4 count changes. Results: 148 people living with HIV (PLWH) were included. The highest rate of immune reconstitution was observed during the first trimester. There was a trend showing that high HIV RNA level resulted in greater increase in CD4 count, especially during the first trimester of cART (difference above vs. below median 15.1 cells/μL/month; 95% CI −1.4–31.5;p= 0.073). Likewise, higher HIV DNA level would predict greater CD4 increases, especially after the first trimester (difference above vs. below median 1.2 cells/μL/month; 95% CI −0.1–2.6;p= 0.071). Higher DNA and RNA levels combined were significantly associated with greater CD4 increase past the first trimester (difference high/high vs. low/low 2.1 cells/μL/month; 95% CI 0.3–4.0;p= 0.024). In multivariable analysis, lower baseline CD4 counts predicted a greater CD4 rise. Conclusions: In successfully treated PLWH, pre-cART HIV DNA and HIV RNA levels are predictors of immune reconstitution.