Physiologic free serum cortisol may more accurately reflect adrenal function than total cortisol levels. Salivary cortisol estimates free serum cortisol. We researched the clinical viability of salivary cortisol in hospitalized patients. Free serum cortisol, and salivary cortisol were measured via ELISA in hospitalized and outpatient patients. We obtained 37/71 satisfactory saliva samples from intensive care unit (ICU) patients. The correlation between free serum, and salivary cortisol over all collected samples was 0.914 (p < 0.001). We identified disparate interpretations for adrenal insufficiency (AI) utilizing total versus free serum cortisol. Salivary cortisol is an acceptable surrogate for free serum cortisol when satisfactory salivary volumes are procured. Due to inadequate sample volumes, and contamination, it should not be generally adopted in the ICU. We identified discordance between free and total cortisol in interpreting AI, suggesting reinterpretation of seminal trials investigating physiologic corticosteroid replacement on the basis of total cortisol levels. The analysis of both free serum cortisol via ultrafiltration and salivary cortisol involved two steps: sample centrifugation followed by ELISA, suggesting consideration of widespread adoption of free serum cortisol in future investigations.