Objectives/Hypothesis To examine the pathogenic bacterial spectra and prognosis of deep neck infection (DNI) in end‐stage renal disease (ESRD) patients. Study Design Retrospective study. Methods Patients diagnosed with DNI between 2004 and 2015 in Chang Gung Memorial Hospital were enrolled and divided into three groups, namely ESRD‐DNI, chronic kidney disease (CKD)‐DNI, and non‐CKD‐DNI. Differences in pathogenic bacteria, treatment, and prognosis were compared across the three groups. Results The bacterial spectra differed among the three groups. The main three facultative anaerobic or aerobic bacteria causing ESRD‐DNIs were methicillin‐resistant Staphylococcus aureus (MRSA; 25.4%), methicillin‐susceptible S. aureus (MSSA; 14.1%), and Klebsiella pneumoniae (KP; 12.7%). For CKD‐DNIs, they were KP (23.5%), Viridans streptococci (VS; 23.5%), and MSSA (14.7%). For non‐CKD‐DNIs, they were VS (31.7%), KP (17.2%), and coagulase‐negative staphylococci (8.0%). Compared with the other groups, the ESRD‐DNI group had higher white blood cell and C‐reactive protein levels, longer hospital stays, more frequent admissions to the intensive care unit, more mediastinal complications, and a significantly higher mortality rate. Conclusions The ESRD‐DNI group exhibited more severe disease activity and higher mortality compared with those of the CKD‐DNI and non‐CKD‐DNI groups. MRSA was the leading pathogen for patients with ESRD‐DNI. Physicians must implement strategies for the early detection of MRSA to accurately prescribe antibiotics and prevent nosocomial transmission. Level of Evidence 4 Laryngoscope, 132:1403–1409, 2022