Background: Acute porphyrias (APs) are a group of rare metabolic diseases related to a disturbed heme biosynthesis. Symptoms may first occur as life threatening attacks, comprising abdominal pain and/or variable neuro-psychiatric symptoms, thus leading to presentation in emergency departments (ED) first. Due to the low prevalence, diagnosis of AP is often missed, even after readmission to the ED. Therefore, strategies are needed to consider APs in ED patients with unexplained abdominal pain, especially since early and adequate treatment will avoid an unfavorable clinical course. Aim of this prospective study was to investigate the prevalence of APs in ED patients and thus, addressing feasibility of screening for rare diseases, such as APs in the real life setting. Methods: From September 2019 to March 2021, patients presenting to the ED of three German tertiary care hospitals with moderate to severe prolonged abdominal pain (Visual Analog Scale, VAS > 4 out of 10 points) not otherwise explained were screened and prospectively enrolled. In addition to standard of care (SOC) diagnostics a blood and urine sample for plasma fluorescence scan and biochemical porphyrin analysis were sent to a certified German porphyria laboratory. Results: Overall, of 653 screened patients, 68 patients (36 females; mean age 36 years) were included for biochemical porphyrin analysis. No patient with AP was detected. The most frequent discharge diagnoses included “abdominal and digestive symptoms” (n = 22, 32%), “gastrooesophageal diseases” (n = 18, 27%), “infectious bowel disease” (n = 6, 9%) and “biliopancreatic diseases” (n = 6, 9%). Although not primarily addressed, we observed an increase in knowledge of the ED staffs at all study sites regarding our screening algorithm and thus, awareness for APs. Conclusions: To the best of our knowledge, we performed the first prospective screening project for APs in the ED. Although we detected no patient with AP in this study, we demonstrated the feasibility of a multicenter screening process for APs by building up a well-working infrastructure comprising laboratory testing as well as data management. This enables the set-up of a larger scale revised follow-up study with a central focus on structured education, thus, possibly acting as blueprint for other rare diseases.