Abstract.Typhoid fever continues to pose a serious health challenge in developing countries. A reliable database on positive blood cultures is essential for prompt interventions. To generate reliable data on Salmonella enterica serovar Typhi (S. Typhi)–positive blood culture trends in typhoidal Salmonella in Nigeria alongside changing contextual factors and antimicrobial resistance patterns, a retrospective cohort study was conducted in two hospitals in Lagos between 1993 and 2015. Medical records of typhoid patients were reviewed for positive culture and antibiogram, using standard procedures and analyzed. Additional data were retrieved from a previous study in seven facilities in Abuja and three hospitals in Kano from 2008 to 2017 and 2013 to 2017, respectively. A declining trend in percent positivity of S. Typhi was observed in Abuja with more erratic trends in Lagos and Kano. In Lagos, more than 80% of the isolates from the entire study period exhibited multiple drug resistance with a generally increasing trend. Of the chosen contextual factors, improvements were recorded in female literacy, access to improved water supply, diarrheal mortality in children younger than 5 years, gross domestic product, and poverty while access to improved sanitation facilities decreased over time nationally. Typhoid fever still poses a serious health challenge in Nigeria and in antibiotic resistance, and is a major health security issue. A combined approach that includes the use of typhoid vaccines, improvements in sanitation, and safe water supply is essential.