The aim was to analyze clinical complications in HIV-infected subjects who persistently maintain low CD4 levels despite virological response to cART in the Spanish CoRIS cohort. The main inclusion criteria were CD4 counts <200 cells/mm3 at cART-initiation and at least 2 years under cART achieving a viral load <500 copies/mL. Those patients with CD4 counts <250 cells/mm3 2 years after cART were classified as the Low-CD4 group, and clinical events were collected from this time-point. Poisson regression models were used to calculate incidence rate ratios of death, AIDS-defining events, serious non-AIDS-defining events (NAE) and of each specific NAE category (non-AIDS-defining malignancies (non-ADM), cardiovascular, kidney- and liver-related events). Of 9667 patients in the cohort, a total of 1128 met the criteria and 287 (25.4%) were classified in the Low-CD4 group. A higher risk of death (aIRR: 4.71; 95% CI: 1.88–11.82; p-value = 0.001) and of non-ADM were observed in this group (aIRR: 2.23; 95% CI: 1.07–4.63; p = 0.03). Our results stress the need to control accelerated aging in this population to counter their increased risk of non-AIDS-defining diseases, particularly cancer, and are consistent with the concept that clinical complications are potentially affected by genetics and lifestyle.