The purpose of this study is to readdress the issue of primary humoral immunodeficiency frequency and pattern in medically resistant chronic rhinosinusitis (CRS) based on the new guidelines for CRS diagnosis and management. Two hundred and fifty-seven consecutive patients with refractory CRS were included in this study. The results of their IgA, IgM, IgG, and IgG subclasses were analyzed and compared with 75 age- and gender-matched control groups. The average age of CRS patients was 34 years (SD ± 13). In the refractory CRS group, there was no significant difference between patients with or without humoral immunodeficiency based on age, gender and status of allergy, polyps and revision. Low level of one of the major immunoglobulin isotypes was found in 15 patients (6 %). Six patients had low IgG, two had low IgA, and seven had low IgM. IgG subclasses were low in 37 patients (14 %), and IgG4 was the most common deficient subclass. Multiple immunoglobulins deficiencies were found in eight patients. Compared with the control group, CRS patients had a significant higher prevalence of major immunoglobulins as well as total major immunoglobulins and IgG subclasses deficiency. Because of high prevalence of subtle humoral immunodeficiency in medically resistant CRS and inability to find unique clinical and demographic characteristic of these patients, we recommend routine screening of major immunoglobulins and IgG subclasses on the group of CRS patients who failed medical treatment.