Objective: Antihistamines are among the most prescribed medicines in otorhinolaryngology. This drug is excellent for rhinorrhea, sneezing and itching, however, it has a debatable effect in rhinosinusitis. At this point, it is useful to examine the relationship between antihistamine and the incidence of sinusitis based on large-cohort data analysis. Design: Retrospective study Setting: A Nationwide cohort study which used population-based insurance data (consisting of data from approximately 1 million patients). Participants: The antihistamine (AH) group consisted of patients who were diagnosed with allergic rhinitis (AR) between January 1, 2003 and December 31, 2003, taking at least one dose of antihistamine. Non-antihistamine (non-AH) group of patients who did not take antihistamines was obtained by 1:4 propensity score matching. Main outcome measures: Primary endpoint was the occurrence of sinusitis. Results: The adjusted hazard ratio for the sinusitis in the AH group was 1.53 [95% CI: 1.36-1.72] compared with the non-AH group. Sinusitis was more frequent in women (HR: 1.34), and less frequent the older the age (HR: 0.74, 0.58, 0.46, respectively) after exposure to antihistamine. In the subgroup analysis regarding the AH usage duration, there was no significant difference between the four subgroups. Conclusion: Antihistamines are probably the most prescribed medicines in the rhinologic area. But as all things have advantages and disadvantages, this large-scale longitudinal study shows that antihistamines are closely associated with sinusitis regardless of prescription duration and thus should be cautiously prescribed.