Introduction Antibiotic prophylaxis is often used as treatment for patients with primary immunodeficiencies (PI) and resistant chronic rhinosinusitis (CRS). We investigated the relationship between antibiotic prophylaxis and resistant organisms cultured on rhinoscopy in these patients. Methods A retrospective review was made of patients with a PI and CRS who had rhinoscopies between April, 2017 and June, 2018. A total of 23 patients were found. Results Seven patients had been treated with antibiotic prophylaxis for time periods ranging from six months to ten years. Six of these patients were found to have resistant organisms on directed endoscopic culture. Of the six patients, one had an IgG subclass deficiency, three had SAD moderate phenotype, and two had SAD mild phenotype. Two patients had MRSA, two had MRSE (including one with sepsis and a culture positive artificial hip aspirate). Others had Pseudomonas, Enterobacter, Proteus, Klebsiella, other resistant S. aureus (not MRSA), and resistant coagulase-negative Staphylococcus. One patient with an IgG subclass deficiency received prophylaxis for 2 years and did not have resistant organisms. Six of the seven patients now receive IgG replacement. Conclusions Caution must be used when treating PI patients with prophylactic antibiotics. Such treatment can create resistant organisms and severely limit future antibiotic options. Although treatment with replacement IgG for patients with less severe SAD is controversial, it has been endorsed by the recent practice parameter and two workgroup reports. In this group of patients, IgG replacement should be considered for patients with resistant disease instead of prophylactic antibiotics.