Relevance. Upper respiratory tract infections (URTIs) are common in children and often progress with secondary complications such as otitis media, bronchitis, or pneumonia, especially in children with recurrent URTIs. Probiotics displayed immunomodulatory effects in children and adults, supporting immune functions to prevent winter diseases or common colds. Objectives. We assessed the effectiveness of a 6-week prophylaxis with probiotics (Lactobacillus helveticus Rosell®-52, Bifidobacterium infantis Rosell®-33 and Bifidobacterium bifidum Rosell®-71) for preventing primary infections and/or secondary complications in URTI-prone children. Methods. URTI-prone children were randomly divided into the probiotics (3×109 CFU/day; 6 weeks) or control arm (no preventive intervention). The number of URTIs, duration and related complications were monitored for 6 months. Resistance index, number of medical visits, and antibiotics prescriptions were also recorded. Results. After 2 months, probiotics reduced the number of URTIs (-2.34±0.13 vs -0.24±0.14; P<0.0001) and duration in (-1.13 ±0.18 vs -0.18±0.18 days; P=0.0011), and the number of secondary complications (-53% vs -5.8%; RR 0.5313 95% CI [0.3534, 0.7986] P= 0.0058). Probiotic lowered resistance index (P<0.0001), number of medical consultations with specialized physicians (P=0.0033) and antibiotics prescriptions (P<0.0001). Conclusions. Overall, a 6-week prophylaxis with combined probiotic (Lactobacillus helveticus Rosell®-52, Bifidobacterium infantis Rosell®-33 and Bifidobacterium bifidum Rosell®-71) in URTI-prone children exerted a significant and clinically important health benefit, decreasing the number and duration of URTI episodes and secondary complications and reducing the resistance index to a near-normal value. Furthermore, potential societal benefits of reducing health care use and inadequate antibiotic prescriptions in children favours the use of this probiotic product as a preventive strategy against URTIs and their consequences in frequently sick children. This trial was retrospectively registered on ClinicalTrials.gov (NCT04525040).