Background: 3DCRT is the most common form of radiotherapy for prostate and bladder cancers, and reducing the uncertainty is becoming critical. Aim: The study aimed to assess the set-up error in the 3-DCRT. Methods: Ten prostate and ten bladder cancer patients were included. Digitally reconstructed radiographs (DRRs) were used to import electronic portal imaging devices (EPID) from radiotherapy planning (RTP) and used for comparison with portal images (PIs) as reference images, which were reconstructed from CT images. The mean displacements between DRRs and EPID were compared (for all images in the three axes). The planning target volume (PTV) margin was calculated using, Stroom, van Herk's formulae, and ICRU report 62. Results: Set-up error was within 9.82 for prostate and 8.36 mm for bladder cancers. The overall mean values of displacements were 7.96, 4.16, and 3.97 mm for the prostate and 6.59, 3.66, and 3.63 mm for the bladder along lateral, vertical, and longitudinal axes, respectively. For the prostate, the systematic error was 4.91, 3.32, and 3.23 mm in Medio-lateral (ML), Anterior-to-Posterior (AP), and superior-inferior (SI) directions. The random error was ML; 6.2, AP; 2.3, and SI; 2.5 mm. For bladder, the systematic error was ML; 4.1, AP; 2.55, and SI; 2.65 mm, while the random error was ML; 4.1, AP; 2.55, and SI; 2.65 mm. The best PTV margin is achieved by using van Herk's formula in all directions for cancers. Conclusions: Set-up alignment protocols should be followed drastically for prostate and bladder cancers in Egyptian RT new centers.