UNLABELLED: Acute respiratory infections (ARI) remain a major cause of child mortality in low- and middle-income countries. However, the risk factors for ARI are poorly understood in low-income settings, and ARI aetiology is changing, driven by vaccination. There are very limited data from Lao PDR (Laos) on ARI aetiology and risk factors to support health policy decisions. This study aimed to investigate the aetiology of hospitalised ARI, and describe risk factors associated with hospitalised ARI, in children under 5 years of age in Laos. We conducted a case–control study at Mahosot Hospital, Laos, enrolling children under five years of age hospitalised with ARI, and community controls matched on age, sex and time of recruitment. Demographics and clinical characteristics were collected, and throat swabs taken. Swabs were analysed using probe-based real-time polymerase chain reaction (PCR) to detect bacterial and viral microorganisms. Risk factors for ARI were determined through regression analysis, and microorganism-specific attributable fractions (AF) were calculated to estimate each microorganism’s contribution to hospitalised ARI. We enrolled 307 cases and 564 controls over 12 months in 2016/17. Microorganisms were detected in 93.8% of cases and 58.9% of controls. Respiratory syncytial virus (RSV) was the leading viral cause of hospitalised ARI, attributed to 29.6% of cases, followed by influenza viruses (11.6%). H. influenzae was attributed to 40.8% of cases. RSV exhibited clear seasonality, peaking during the wet season. Exclusive breastfeeding for 3 months (OR: 0.62; 95% CI 0.45–0.86), and being up to date with pneumococcal conjugate vaccination (odds ratio: 0.6; 95% CI 0.41–0.80), were associated with a lower risk of hospitalised ARI; while low birth weight (OR: 2.91; 95% CI 1.63–5.28), and household smoking (OR: 3.07; 95% CI 2.25–4.18), were associated with increased risk. RSV and H. influenzae remain major causes of ARI in Laos. The findings highlight the potential benefit of tailoring interventions to the local context, including vaccination and risk mitigation strategies, to reduce the burden of ARI in Laos and other low and middle-income countries. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41321-9.