Serum antibodies play an important role in natural protection from rotavirus infection and disease, but conflicting estimates of association have emerged from epidemiological studies in different geographical settings. In this study, we aim to assess the relationship between pre-existing serum immunoglobulin (Ig)G and IgA titers with protection against rotavirus infection and disease in a birth cohort of Indian children. Children were recruited at birth and followed up for 36 months. Stool samples were collected every 2 weeks and during episodes of diarrhea and serum samples were obtained at least every 6 months. The incidence rate of rotavirus infection and diarrhea was 0.9 (95% CI: 0.88, 0.99) and 0.2 (95% CI: 0.19, 0.25) episodes per child year, respectively. The risk of rotavirus infection and diarrhea decreased with age, while antibody titers (IgG and IgA) increased with age. After adjusting for age and number of previous infections, higher levels of IgG and IgA were independently associated with reduced risk of rotavirus infection. However, we did not find a clear association of IgG or IgA with rotavirus diarrhea risk or a threshold level of protection. The study supports a correlation of serum antibodies in reducing the risk of rotavirus infections, however the potential of serum antibody titer as a correlate of protection is not clear for children in lower income settings.