Background Dual-energy CT iodine maps are used to detect pulmonary embolism (PE) with CT angiography but require dedicated hardware. Subtraction CT, a software-only solution, results in iodine maps with high contrast-to-noise ratios. Purpose To compare the use of subtraction CT versus dual-energy CT iodine maps to CT angiography for PE detection. Materials and Methods In this prospective study ( https://clinicaltrials.gov , NCT02890706), 274 participants suspected of having PE underwent precontrast CT followed by contrast material-enhanced dual-energy CT angiography between July 2016 and April 2017. Iodine maps from dual-energy CT were derived. Subtraction maps (contrast-enhanced CT minus precontrast CT) were calculated after motion correction. Truth was established by expert consensus. A total of 75 randomly selected participants with and without PE (1:1 ratio) were evaluated by three radiologists and six radiology residents (blinded to final diagnosis) for the presence of PE using three types of CT: CT angiography alone, dual-energy CT, and subtraction CT. The partial area under the receiver operating characteristic curve (AUC) for the clinically relevant specificity region (maximum partial AUC, 0.11) was compared by using multireader multicase variance. A P value less than or equal to .025 was considered indicative of a significant difference due to multiple comparisons. Results There were 35 men and 40 women in the reader study (mean age, 63 years ± 12 [standard deviation]). The pooled sensitivities were not different (P ≥ .31 among techniques) (95% confidence intervals [CIs]: 67%, 89% for CT angiography; 72%, 91% for dual-energy CT; 70%, 91% for subtraction CT). However, pooled specificity was higher for subtraction CT (95% CI: 100%, 100%) than for CT angiography (95% CI: 89%, 97%) or dual-energy CT (95% CI: 89%, 98%) (P < .001). Partial AUCs for the average observer improved equally when adding iodine maps (subtraction CT [0.093] vs CT angiography [0.088], P = .03; dual-energy CT [0.094] vs CT angiography, P = .01; dual-energy CT vs subtraction CT, P = .68). Average reading times were equivalent (range, 97-101 seconds; P ≥ .41) among techniques. Conclusion Subtraction CT iodine maps had greater specificity than CT angiography alone in pulmonary embolism detection. Subtraction CT had comparable diagnostic performance to that of dual-energy CT, without the need for dedicated hardware. © RSNA, 2019 Online supplemental material is available for this article.