: Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are the primary tools for malaria prevention in Africa. It is not known whether reductions in malaria can be sustained after IRS is discontinued. The aim of this study was to assess changes in malaria morbidity in a historically high transmission area of Uganda where IRS was discontinued after a four-year period of effective control followed by a universal LLIN distribution campaign.<br/> : Individual-level malaria surveillance data were collected from one outpatient department and one inpatient setting in Apac District, Uganda from July 2009 through November 2015. Rounds of IRS were delivered approximately every six months from February 2010 through May 2014 followed by universal LLIN distribution in June 2014. Temporal changes in the malaria test positivity rate (TPR) were estimated during and after IRS using interrupted time series analyses, controlling for age, rainfall, and autocorrelation.<br/> : Data include 65,421 outpatient visits and 13,955 pediatric inpatient admissions for which a diagnostic test for malaria was performed. In outpatients under five years, baseline TPR was 60-80% followed by a rapid and then sustained decrease to 15-30%. Over 4-18 months following discontinuation of IRS, absolute TPR values increased by an average of 3.29% per month (95% CI 2.01-4.57%), returning to baseline levels. Similar trends were seen in outpatients over five years of age and pediatric admissions.<br/> : Discontinuation of IRS in a historically high transmission intensity area was associated with a rapid increase in malaria morbidity to pre-IRS levels.<br/>