Direct Healthcare Professional Communication (DHPC) is essentially distributed for fast communication of new serious drug safety information to healthcare professionals (HCPs). However, the use of this tool concerning the knowledge and preferences of HCPs has never been evaluated in Egypt. This study aimed to evaluate the HCPs' knowledge, preferences, and barriers to the use of DHPC in Egypt. A cross-sectional study of a random sample of 254 HCPs surveyed via face-to-face interviews to assess the Egyptian HCPs' awareness of DHPC, the preferences, and barriers that affect its use. Among the 297 approached HCPs, only 254 accepted to participate with a response rate of 85.5%, including (50% internists, 22.83% cardiologists, 11.02% neurologists, 11.02% pediatricians, and 5.12% from other specialties). Most HCPs were not familiar with DHPC (N= 254, 61.8%). One-third of the visited HCPs who were aware of concerned drugs' risk(s) got their information from DHPC (N= 149, 36.9%). HCPs preference for communication channel was highest for meetings (N= 254, 65.7%) and least for newsletters (N= 254, 28%). HCPs reported barriers to reading DHPC included; busy schedule (N= 254, 47.6%), mistrusted source (N= 254, 24.4%), view as a marketing tool (N= 254, 21.7%), invaluable information (N= 254, 9.8%) and disbelief (N= 254, 7.5%). The DHPC did not reach the target HCPs most of the time, but when received, it was successful in conveying the required message to the target HCPs. Multiple barriers were identified that negatively impacted the success of DHPC. It is recommended to use other electronic communication methods to enhance the reachability of the current method (DHPC).