Introduction Computed tomography angiography (CTA) and ventilation/perfusion (V/Q) single photon emission computed tomography/CT (SPECT/CT) images have been widely used to detect PE, but few studies have performed a direct comparison between them. We aimed to evaluate the performance of these tests in the same group of patients, selected from the routine practice of a general hospital. Methods Patients with suspected acute PE were prospectively submitted to CTA and V/Q SPECT/CT. General radiologists and nuclear physicians, respectively, interpreted the images. Data regarding age, sex, time between examinations, symptoms, and Wells score were also recorded. The final diagnosis was decided through a consensus among the clinicians, taking into account clinical, laboratory, follow-up, and all imaging procedures data. Results Twenty-eight patients (15 male, 13 female, and median age of 51.5 years) were studied. Median duration of the onset of symptoms was 4 (1–14) days, and the median Wells score was 3.5 (1.5–6). Sensitivity, specificity, positive and negative predictive values, and accuracy were 84.6%, 80.0%, 78.6%, 85.7%, and 82.1% for V/Q SPECT/CT, and 46.1%, 100%, 100%, 68.2%, and 75.0% for CTA. The overall agreement between the methods was 57.1%. Of the 22 patients with negative CTA, 10 (45.4%) had positives V/Q SPECT/CT and seven of them classified as true positives. Conclusions Our results suggest that V/Q SPECT/CT is more sensitive and accurate than CTA when interpreted by general radiologists and nuclear medicine physicians.