Unexpected pericardial effusions are often found by frontline providers who perform computed tomography. To study the hypothesis that electrocardiographic findings and whether cancer is known or suspected importantly change the likelihood of tamponade for such providers, all unique patients with moderate or large pericardial effusions determined by transthoracic echocardiography during a 6-year period were retrospectively identified. Electrocardiograms were evaluated by blinded investigators for electrical alternans (total and QRS), low voltage (limb leads only, precordial leads only, and both), and tachycardia (>100 QRS complexes/min). Medical records were reviewed to determine whether cancer was known or suspected and whether tamponade was diagnosed. Tamponade was present in 66 patients (27% of 241) with moderate or large pericardial effusions. No tachycardia lowered the odds of tamponade the most (likelihood ratio 0.4, 95% confidence interval 0.3 to 0.6) but by a degree less than any single diagnostic element increased it when present. The combined presence of all 3 electrocardiographic findings and cancer increased the odds of tamponade 63-fold (likelihood ratio 63, 95% confidence interval 33 to 150), whereas their combined absence decreased the odds only fivefold (likelihood ratio 0.2, 95% confidence interval 0.2 to 0.3). In conclusion, electrocardiography findings and cancer rule in tamponade better than they rule it out. Combining these diagnostic elements improves their discriminatory power but not sufficiently enough to rule out tamponade in patients with moderate or large pericardial effusions.