Abstract Background The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. Methods This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. Results Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval CI, 5.88–9.08), 5.50 (95% CI, 4.21–7.07), and 2.87 (95% CI, 2.18–3.70) cases/100 person-years in children aged 0–5, 6–11, and 12–23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0–5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0–2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. Conclusions A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175. In a prospective, observational cohort study conducted in 8 countries across diverse settings, we found that RSV-LRTI burden is substantial during the first 2 years of life and tends to be higher among 0–5 month olds and in lower-income settings. Graphical Abstract Graphical Abstract Lay Summary Respiratory syncytial virus (RSV) is a common pathogen that causes respiratory illnesses. Although symptoms are usually mild, young children can have more serious diseases such as bronchiolitis and pneumonia. The number of children with RSV illnesses and the need for health care differ by country and are likely underestimated. In a study conducted in 8 countries, we followed 2401 children from birth to 2 years to determine the frequency of lower respiratory tract infections (LRTIs) and hospitalizations due to RSV. We found that 206 children had these infections. Approximately 7 in 100 children had an RSV-LRTI in the first 6 months of life. Furthermore, the youngest children had more serious symptoms and were hospitalized more often than children older than 6 months. While RSV-LRTI incidence and hospitalization rates varied among countries, they were higher in low- or middle-income countries or regions than in high-income countries. We found that approximately 1 in 3 children with RSV-LRTIs also had other viruses that could cause respiratory illness. These results show that children younger than 2 years are greatly affected by RSV, especially in low- and middle-income countries. Programs to prevent RSV infections in young children around the world would likely bring health benefits.