The new Cabotegravir + Rilpivirine long acting (CAB + RPV) is the injectable regimen for treatment-experienced people with HIV (PWH). Little data from real-world settings are available, particularly in more complex PWH. We aimed to investigate the effectiveness of CAB + RPV in our real-life cohort of experienced PWH. We conducted a prospective observational longitudinal study by enrolling PWH who switched to CAB + RPV. We recruited participants from our outpatient clinic and a lower percentage of complex PWH followed by our home-care assistance (HCA). We evaluated time to virological failure (VF) and time to treatment discontinuation (TD) for any cause using Cox regression analyses. In the subgroup followed by HCA we also analyzed the total HIV-DNA trend during the study period. We enrolled 62 participants: 52 were outpatients (83.9%) and 10 followed by HCA (16.1%). Mostly were males (66.1%), with a median age of 51 years (IQR 31-60). During a 31.5 person-years follow-up (PYFU), all participants maintained virological suppression (< 30cps/mL). We observed 9 discontinuations during follow-up, with a rate of discontinuation of 28.6 per 100 PYFU. The estimated probabilities of maintaining CAB + RPV at 24 and 48 weeks were 84.9% (SD: 0.5) and 79.2% (SD: 0.7), respectively. No significant predictors of discontinuations were found. In the subgroup, we found no significant changes in the HIV-DNA levels over time (p = 0.332). Our results confirm the efficacy of CAB + RPV as a switch strategy in virologically suppressed PWH and even in more complex individuals, encouraging its use in PWH in need, coupled with HCA home administration support.