Purpose: Clinical examination is often the first step to diagnose shock and estimate cardiac index. In the Simple Intensive Care Studies-I, we assessed the association and diagnostic performance of clinical signs for estimation of cardiac index in critically ill patients. Methods: In this prospective, single-centre cohort study, we included all acutely ill patients admitted to the ICU and expected to stay > 24 h. We conducted a protocolised clinical examination of 19 clinical signs followed by critical care ultrasonography for cardiac index measurement. Clinical signs were associated with cardiac index and a low cardiac index (< 2.2 L min −1 m 2) in multivariable analyses. Diagnostic test accuracies were also assessed. Results: We included 1075 patients, of whom 783 (73%) had a validated cardiac index measurement. In multivariable regression, respiratory rate, heart rate and rhythm, systolic and diastolic blood pressure, central-to-peripheral temperature difference, and capillary refill time were statistically independently associated with cardiac index, with an overall R 2 of 0.30 (98.5% CI 0.25-0.35). A low cardiac index was observed in 280 (36%) patients. Sensitivities and positive and negative predictive values were below 90% for all signs. Specificities above 90% were observed only for 110/280 patients, who had atrial fibrillation, systolic blood pressures < 90 mmHg, altered consciousness, capillary refill times > 4.5 s, or skin mottling over the knee. Conclusions: Seven out of 19 clinical examination findings were independently associated with cardiac index. For estimation of cardiac index, clinical examination was found to be insufficient in multivariable analyses and in diagnostic accuracy tests. Additional measurements such as critical care ultrasonography remain necessary.