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Background Influenza is a cause of febrile acute respiratory infection (FARI) in India; however, few influenza vaccine trials have been conducted in India. We assessed absolute and relative efficacy of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) among children aged 2 to 10 years in rural India through a randomized, triple-blind, placebo-controlled trial conducted over 2 years. Methods and findings In June 2015, children were randomly allocated to LAIV, IIV, intranasal placebo, or inactivated polio vaccine (IPV) in a 2:2:1:1 ratio. In June 2016, vaccination was repeated per original allocation. Overall, 3,041 children received LAIV (n = 1,015), IIV (n = 1,010), nasal placebo (n = 507), or IPV (n = 509). Mean age of children was 6.5 years with 20% aged 9 to 10 years. Through weekly home visits, nasal and throat swabs were collected from children with FARI and tested for influenza virus by polymerase chain reaction. The primary outcome was laboratory-confirmed influenza-associated FARI; vaccine efficacy (VE) was calculated using modified intention-to-treat (mITT) analysis by Cox proportional hazards model (PH) for each year. In Year 1, VE was 40.0% (95% confidence interval (CI) 25.2 to 51.9) for LAIV and 59.0% (95% CI 47.8 to 67.9) for IIV compared with controls; relative efficacy of LAIV compared with IIV was −46.2% (95% CI −88.9 to −13.1). In Year 2, VE was 51.9% (95% CI 42.0 to 60.1) for LAIV and 49.9% (95% CI 39.2 to 58.7) for IIV; relative efficacy of LAIV compared with IIV was 4.2% (95% CI −19.9 to 23.5). No serious adverse vaccine-attributable events were reported. Study limitations include differing dosage requirements for children between nasal and injectable vaccines (single dose of LAIV versus 2 doses of IIV) in Year 1 and the fact that immunogenicity studies were not conducted. Conclusions In this study, we found that LAIV and IIV vaccines were safe and moderately efficacious against influenza virus infection among Indian children. Trial registration Clinical Trials Registry of India CTRI/2015/06/005902., Anand Krishnan and co-workers study the efficacy and safety of influenza vaccines for children in India., Author summary Why was this study done? In recent years, 2 community-based trials of the single-dose Russian-backbone live attenuated influenza vaccine (LAIV) in low- and middle-income countries (LMIC) have been published, with contrasting results. In Senegal, LAIV vaccine efficacy (VE) was demonstrated to be 0.0% (95% confidence interval (CI) −26.4 to 20.9), and in Bangladesh, LAIV VE was demonstrated to be 41.0% (95% CI 28.0 to 51.6) against all influenza virus strains. In addition, observational studies for VE of LAIV such as in the United States and Europe have also shown mixed results. While the World Health Organization (WHO) continues to recommend LAIV use in children, conflicting data on LAIV have led countries to review and reconsider national preferential recommendations for LAIV use in children. Given these gaps in evidence and the potential for indigenously produced LAIV to be used for prevention of influenza virus infection in Indian children, we evaluated the absolute efficacy of LAIV and inactivated influenza vaccine (IIV) and relative efficacy of LAIV versus IIV among children aged 2 to 10 years in rural India. What did the researchers do and find? We conducted a 2-year, triple (participant–observer–analyst) blind, community-based vaccine trial. We randomly assigned 3,041 children aged 2 to 10 years to receive age appropriate doses of LAIV, IIV, or a control vaccine. In Year 1, VE was 40.0% (95% CI 25.2 to 51.9) for LAIV and 59.0% (95% CI 47.8 to 67.9) for IIV compared with controls; relative efficacy of LAIV compared with IIV was −46.2% (95% CI −88.9 to −13.1). In Year 2, VE was 51.9% (95% CI 42.0 to 60.1) for LAIV and 49.9% (95% CI 39.2 to 58.7) for IIV; relative efficacy of LAIV compared with IIV was 4.2% (95% CI −19.9 to 23.5). We found that LAIV and IIV were safe and moderately efficacious against laboratory-confirmed influenza virus infection. In Year 1, LAIV, as a single dose in a vaccine-naïve population, was significantly less efficacious than IIV, whereas in Year 2, VE for LAIV and IIV was similar. This was the first randomized controlled trial to our knowledge in a developing country setting that compared LAIV efficacy with IIV and provided VE by age group and influenza type/subtype across seasons spanning 2 consecutive years. Importantly, during both years, LAIV and IIV were protective against influenza A(H3N2) viruses. However, LAIV had limited efficacy against influenza A(H1N1)pdm09 for both years. What do these findings mean? Influenza vaccination is an important tool for preparedness and response against seasonal epidemics and pandemics. However, decisions on specific vaccine introductions into national immunization platforms depend on multiple factors including effectiveness, presence of existing immunization platforms and cold chain infrastructure, cost, and local production of the vaccines. Availability of indigenous, safe, and moderately efficacious influenza vaccines, including LAIV, should initiate discussion on the optimal use of vaccines for the national strategy for influenza prevention and control in India.