To investigate the effects of ventilatory mode, injectate temperature, and clinical situation on the precision of cardiac output measurements. Randomized, prospective observational study. Single university hospital. Forty patients undergoing planned cardiac surgery, receiving a pulmonary artery catheter according to institutional routine. Cardiac output was measured at 4 predefined time points during the perioperative patient course, twice during controlled and twice during spontaneous ventilation, using 2 blocks of 8 measurement replications with cold and tepid injectate in random order. The data were analyzed using a hierarchical linear mixed model. Clinical precision was determined as half the width of the 95% confidence interval for the underlying true value. The single-measurement precision measured in 2 different clinical situations for each temperature/ventilation combination was 8% to 10%, 11% to 13%, 13% to 15%, and 23% to 24% in controlled ventilation with cold injectate, controlled ventilation with tepid injectate, spontaneous breathing with cold injectate, and spontaneous breathing with tepid injectate, respectively. Tables are provided for the number of replications needed to achieve a certain precision and for how to identify significant changes in cardiac output. Clinical precision of cardiac output measurements is reduced significantly during spontaneous relative to controlled ventilation. The differences in precision between repeated measurement series within the temperature/ventilation combinations indicate influence of other situation-specific factors not related to ventilatory mode. Compared with tepid injectate in patients breathing spontaneously, the precision is 3-fold better with cold injectate and controlled ventilation.