Background: Despite the high rate of virological success of combined antiretroviral therapy (cART), HIV infected individuals continue to fail. In this contest, it is unclear whether having previously experienced virological failure (VF)of cART remains an important predictor of future risk of VF in people receiving cART in modern times. We investigated the rate of VF and factors potentially associated with this event in 9220 HIV-1 infected patients enrolled in the Icona Cohort who showed a stable viral suppression on modern cART regimens after January 1, 2006. Methods: We investigated two main exposure factors: current calendar period (2006–2009; 2010–2013; 2014–2017)and number of VFs (0; 1–3; >3)prior to baseline. Relative rates of VF were estimated from fitting a Poisson regression model. Results: Seven-hundred-seventy-nine patients experienced VF over follow-up for an overall rate of 2.08 per 100 person years of follow-up (PYFU, 95%CI: 1.93–2.22). The rate of VF increased with higher numbers of previous VFs: patients with >3 previous VFs had a rate of 4.87 (4.10–5.78), 2.75-fold higher than that observed in patients without any previous VF (p < 0.001). The rate of VF was lower in recent years: 3.81 (3.36, 4.32)in 2006–2009; 1.36 (1.20–1.53)in 2014–2017 (p < 0.001). Other factors independently associated with lower risk of VF were Italian origin, longer history of virological suppression, and university education level. Conclusions: In HIV-infected patients virologically suppressed after January 2006, the rate of VF continues to show a decline even in the most recent years. Previous VFs should be carefully considered.