In treating lower urinary tract symptoms (LUTS), the risk of overtreatment with antibiotics must be reconciled with the risk of an untreated urinary tract infection (UTI) progressing to acute pyelonephritis (APN). Using Cerner HealthFacts, a longitudinal clinical informatics database, we aimed to determine risk factors associated with the development of APN from UTI in an effort to guide the initiation of empiric antibiotics. We queried the Cerner HealthFacts database for women over age 18 with a positive urine culture. Any patient with an International Classification of Disease (ICD) code indicating chronic pyelonephritis was excluded. Development of APN within 30 days of the positive culture, specified by ICD coding, was our primary outcome. Patient and facility factors were assessed as potential risk factors for the development of APN using multivariable regression. Out of 58 344 women with a positive urine culture, 3.9% (2296) developed APN. Mean patient age was 54.4 ± 25.3 years. Overall, 12 variables were predictive for APN and 11 variables were protective against APN. Presence of obstructive and reflux uropathies (OR 4.58), presentation to an acute care facility (OR 3.19), urinary retention (OR 2.30), history of UTI (OR 2.19), and renal comorbidities (OR 2.07) conferred the highest odds of APN development. The most protective variable against APN development was cognitive impairment (OR 0.49). Identified risk factors associated with APN development may aid decisions regarding empiric antibiotic initiation for patients presenting with LUTS while awaiting urine culture results. The relationship between cognitive impairment and progression to APN deserves further study.