OBJECTIVES: To evaluate the clinical effectiveness of the 2009-2010 seasonal influenza vaccine in preventing Influenza-like illness (ILI) in healthy Indian children of age 6 months to 18 years. METHODS: A prospective observational cohort study was carried out from September, 2009 to February, 2010, at a private outpatient pediatric setting in Northern India. All the enrolled children were followed monthly through telephonic interview of their parents for development of ILI. The visits to physician for any acute respiratory tract infection (ARI) were also recorded. ILI was defined as per ICD-10. Children having 1 shot and 2 shots of influenza vaccine were defined as partially vaccinated and fully vaccinated, respectively. Multiple logistic regression was used to calculate the association between vaccination status and ILI.  RESULTS: A total of 294 children, vaccinated cohort (N=153) and unvaccinated cohort (N=141) were enrolled in the study. There was a statistically significant reduction in ILI [OR 0.57 (0.33-0.99), P <0.05] and visits to physician for ARI [OR 0.42 (0.22-0.79), P <0.05] among fully vaccinated children (n=101) when compared to unvaccinated children (n=141). Secondly, there was no significant reduction in ILI and visits to physician among partially vaccinated children (n=52) versus unvaccinated children [OR 1.54 (0.77-3.07), P=0.24 and OR 1.81 (0.65-5.27), P=0.30] respectively. CONCLUSIONS: Based upon these findings, it is concluded that seasonal influenza vaccine is effective in reducing the ILI and visits to physician for ARI among fully vaccinated Indian children. Partially vaccinated children had no statistically significant protection against ILI and visits to physician.  To the best of our knowledge, this is the first report on the clinical effectiveness of seasonal influenza vaccine in healthy Indian children.