A very high incidence of typhoid was described in studies conducted in urban locations on the Indian subcontinent at the end of the twentieth century. Despite their availability, licensed immunogenic conjugate typhoid vaccines have not been introduced in the national immunization program, in part, because of a lack of understanding of where and for whom prevention is most necessary. Uncertainty regarding the burden of disease is based on the lack of reliable, recent estimates of culture-confirmed typhoid and an observed trend of low isolations of Salmonella Typhi and fewer complications at large referral hospitals in India. In this article, we examine the trends of S. Typhi isolation at three large tertiary care centers across India over 15 years and describe trends of recognized risk factors for typhoid from published literature. There appears to be a decline in the isolation of S. Typhi in blood cultures, which is more apparent in the past 5 years. These trends are temporally related to economic improvement, female literacy, and the use of antibiotics such as cephalosporins and azithromycin. The analysis of trends of culture-confirmed typhoid may not accurately capture the typhoid incidence trends if antibiotic use confounds the burden of disease presenting to larger facilities. Emerging antimicrobial resistance may result in a resurgence of disease if the underlying incidence and transmission of typhoid are not adequately addressed through public health approaches.