Appropriate testing of blood procalcitonin (PCT) can potentially inform antibiotic de-escalation in patients with severe infections. When used along with observed clinical improvements, PCT testing can support antimicrobial stewardship. However, this testing must be used optimally to ensure that it is actionable, cost-effective, and provides patient benefit. Although this test is widely used, little is known about the appropriateness of this testing in select populations. Methods: In this retrospective review, we evaluated PCT monitoring patterns and appropriateness of use and relationship to antibiotic days of therapy in a system of community hospitals. We evaluated the use of PCT testing in patients with known confounders, namely pregnancy, chronic kidney disease, or neutropenia, which we classified as “inappropriate use” because these conditions can affect the interpretation of PCT results. We also evaluated the relationship between PCT testing and antibiotic days of therapy for patients with sepsis, pneumonia, or lower respiratory tract infections. Results: In a 1-year period, ∼206,302 PCT tests were performed at 146 facilities, an average of ∼1,413 per facility per year. Approximately 27.7% of these tests were given to patients who were pregnant or had a confounding comorbidity such as chronic kidney disease or neutropenia. Of these “inappropriate” tests, >90% were given to patients with chronic kidney disease. Older patients (aged 60–80 years, n = 93,021) were more likely to receive a PCT test while also having a confounding comorbidities; 24% of older patients with a PCT test also had chronic kidney disease. Of all patients with a PCT test and chronic kidney disease, ∼76% were also diagnosed with either sepsis, pneumonia, or lower respiratory tract infections. Conclusions: Confounding conditions can affect PCT levels independently of infection. Additionally, some clinicians use PCT tests as probes for other physiological maladies. This analysis demonstrated that there is opportunity for education about the appropriate use of this test, how to interpret results in the presence of confounding conditions, and how to transform PCT test results into actions that facilitate antimicrobial stewardship and better patient care.