Abstract Background Cabotegravir (CAB) + rilpivirine (RPV) dosed monthly or every 2 months is a complete long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Across the Phase 3/3b trials, the most frequently reported adverse events were injection site reactions (ISRs). Methods We present pooled ISR characteristics and outcomes for participants receiving CAB+RPV LA through Week 96 of the FLAIR and ATLAS-2M studies, and survey results from healthcare providers (HCPs) giving injections (e.g. injectors) in the ATLAS, FLAIR, and ATLAS-2M studies to determine optimal injection techniques. Surveys were anonymous, self-administered online questionnaires that queried provider demographics, injection experience, and techniques to minimize pre-/post-injection discomfort. Data were summarized using descriptive statistics. Results Overall, 8453 ISRs were reported by 801 participants receiving ≥1 injection of CAB LA/RPV LA. Most ISRs were mild to moderate in severity (Grade 1–2, 99%), with a median (interquartile range) duration of 3 days (2–4), and rarely led to withdrawal (2%). Surveys were completed by 181 HCPs across 113 sites. Pushing the intramuscular injection at slow speed (66%), bringing the medication to room temperature (58%), and relaxing the gluteus muscle before injecting (53%) were ranked as effective pre-injection/injection procedure practices for minimizing pain. Most injectors (60%) indicated that a prone position provided optimal patient comfort, and 41% had no preference on injection medication order. Conclusions Taken together, the data demonstrating favorable tolerability with CAB+RPV LA injections over the long term and simple techniques routinely used by injectors to help optimize the administration of CAB+RPV LA injections.