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Background Salmonella enterica serovar Typhi is transmitted by fecally contaminated food and water and causes approximately 22 million typhoid fever infections worldwide each year. Most cases occur in developing countries, where approximately 4% of patients develop intestinal perforation (IP). In Kasese District, Uganda, a typhoid fever outbreak notable for a high IP rate began in 2008. We report that this outbreak continued through 2011, when it spread to the neighboring district of Bundibugyo. Methodology/Principal Findings A suspected typhoid fever case was defined as IP or symptoms of fever, abdominal pain, and ≥1 of the following: gastrointestinal disruptions, body weakness, joint pain, headache, clinically suspected IP, or non-responsiveness to antimalarial medications. Cases were identified retrospectively via medical record reviews and prospectively through laboratory-enhanced case finding. Among Kasese residents, 709 cases were identified from August 1, 2009–December 31, 2011; of these, 149 were identified during the prospective period beginning November 1, 2011. Among Bundibugyo residents, 333 cases were identified from January 1–December 31, 2011, including 128 cases identified during the prospective period beginning October 28, 2011. IP was reported for 507 (82%) and 59 (20%) of Kasese and Bundibugyo cases, respectively. Blood and stool cultures performed for 154 patients during the prospective period yielded isolates from 24 (16%) patients. Three pulsed-field gel electrophoresis pattern combinations, including one observed in a Kasese isolate in 2009, were shared among Kasese and Bundibugyo isolates. Antimicrobial susceptibility was assessed for 18 isolates; among these 15 (83%) were multidrug-resistant (MDR), compared to 5% of 2009 isolates. Conclusions/Significance Molecular and epidemiological evidence suggest that during a prolonged outbreak, typhoid spread from Kasese to Bundibugyo. MDR strains became prevalent. Lasting interventions, such as typhoid vaccination and improvements in drinking water infrastructure, should be considered to minimize the risk of prolonged outbreaks in the future., Author Summary Typhoid fever is an acute febrile illness caused by the bacteria Salmonella Typhi and transmitted through food and water contaminated with the feces of typhoid fever patients or carriers. We investigated typhoid fever outbreaks in two neighboring Ugandan districts, Kasese and Bundibugyo, where typhoid fever outbreaks began in 2008 and 2011, respectively. In Kasese from August 2009–December 2011, we documented 709 cases of typhoid fever. In Bundibugyo from January–December 2011, we documented 333 cases. Salmonella Typhi from Bundibugyo and Kasese had indistinguishable molecular fingerprints; laboratory and epidemiological evidence indicate that the outbreak spread from Kasese to Bundibugyo. Salmonella Typhi isolated during our investigation were resistant to more antibiotics than isolates obtained from Kasese in 2009. Drinking water in both districts was fecally contaminated and the likely vehicle for the outbreaks. Our investigation highlights that in unchecked typhoid fever outbreaks, illness can become geographically dispersed and outbreak strains can become increasingly resistant to antibiotics. Lasting interventions, including investments in drinking water infrastructure and typhoid vaccination, are needed to control these outbreaks and prevent future outbreaks.