Objectives/Hypothesis To look for predictors of respiratory epithelial adenomatoid hamartomas (REAH) development in patients operated for nasal polyposis (NP) by adjusting on confounding factors. Study Design Prospective study. Methods One hundred and six patients with NP, endoscopically operated between September 2009 and March 2012 on the ethmoidal labyrinths and olfactory clefts, were enrolled in this study. Clinical data was collected 1 day prior to surgery by using a standard grid without knowledge of any histological features. Patients were then divided into two groups based on operative and pathological reports: with and without REAH in the olfactory cleft (REAH-OC). The multivariate logistic regression model was used to assess independent factors linked to the presence of REAH-OC in patients with NP. Results The mean duration of NP disease in patients with REAH-OC was about 13.95 ± 10.8 years versus 5.7 ± 5.6 years in patients without REAH-OC (P < 0.0001). Seventy-four percent of patients with REAH-OC had undergone one or more NP-related surgeries in their lifetime, in contrast with 49.21% of patients without REAH-OC (P = 0.009). According to the multivariate logistic regression analysis, those patients experiencing NP ≥ 10 years (OR 4.0, 95% CI 1.304–12.062, P = 0.015) and those with asthma (OR 2.5, 95% CI 1.004–6.29, P < 0.05) were at an increased risk of developing REAH-OC. Conclusion The development of REAH in patients with NP appears as a specific disease of the mucosa of the OC, induced by a long-lasting and/or severe inflammation of the olfactory clefts.