© TÜBİTAK.Background/aim: The differences in molecular mechanisms during a stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different predefined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Materials and methods: Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Results: Serum IL-13, IL-25, TSLP, and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients, and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309–8427) pg/mL vs. 4479 (2766–6495) pg/mL; p = 0.05] and periostin levels were much lower in viral infection-induced exacerbations [2913 (893–4770) pg/mL vs. 7094 (4782–9596) pg/mL; p = 0.022]. Conclusion: Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long-term systemic steroid use.