Purpose: To investigate critical aspects and effectiveness of in vivo dosimetry (IVD) tests obtained by an electronic portal imaging device (EPID) in a multicenter and multisystem context. Materials and methods: Eight centers with three commercial systems—SoftDiso (SD, Best Medical Italy, Chianciano, Italy), Dosimetry Check (DC, Math Resolution, LCC), and PerFRACTION (PF, Sun Nuclear Corporation, SNC, Melbourne, FL)—collected IVD results for a total of 2002 patients and 32,276 tests. Data are summarized for IVD software, radiotherapy technique, and anatomical site. Every center reported the number of patients and tests analyzed, and the percentage of tests outside of the tolerance level (OTL%). OTL% was categorized as being due to incorrect patient setup, incorrect use of immobilization devices, incorrect dose computation, anatomical variations, and unknown causes. Results: The three systems use different approaches and customized alert indices, based on local protocols. For Volumetric Modulated Arc Therapy (VMAT) treatments OTL% mean values were up to 8.9% for SD, 18.0% for DC, and 16.0% for PF. Errors due to “anatomical variations” for head and neck were up to 9.0% for SD and DC and 8.0% for PF systems, while for abdomen and pelvis/prostate treatments were up to 9%, 17.0%, and 9.0% for SD, DC, and PF, respectively. The comparison among techniques gave 3% for Stereotactic Body Radiation Therapy, 7.0% (range 4.7–8.9%) for VMAT, 10.4% (range 7.0–12.2%) for Intensity Modulated Radiation Therapy, and 13.2% (range 8.8–21.0%) for 3D Conformal Radiation Therapy. Conclusion: The results obtained with different IVD software and among centers were consistent and showed an acceptable homogeneity. EPID IVD was effective in intercepting important errors. © 2021, Springer-Verlag GmbH, DE part of Springer Nature.