Healthy physiological systems exhibit irregular variability whereas diseased systems display decreased signal variability or greater regularity. The objective of this article is to report a case series of critically ill adults who displayed ultra low-frequency periodic sinusoidal oscillations in cardiac output (ULF-CO) that were discovered during a clinical study testing software for continuous physiological monitoring. Data were collected from 13 critically ill surgical and trauma patients who required continuous cardiac output monitoring. Physiologic data were collected from clinical monitors. The computerized time series of cases displaying CO oscillations were manually reviewed. Ten patients with sepsis or the systemic inflammatory response syndrome exhibited 18 episodes of ultra low-frequency periodic oscillations (ULF-CO) with frequencies ranging from 0.0028 to 0.000053 Hz (periods, 6 to 316 min). Intensive care unit mortality rate was 50%. The amplitude and coefficient of variation of cardiac output during ULF-CO ranged from 0.1-4.6 L and 3.9-14.3%, respectively. Duration of ULF-CO ranged from 4-108.1 h. ULF-CO could not be explained as a result of patterned artifact from measurement error or therapeutic intervention. ULF-CO may be a pathophysiologic marker that might serve the diagnosis, prognosis, and treatment of critical illness.