Alongside with inflammation, increased airway resistance is a key feature of obstructive lung diseases. The data accumulated up to date suggest that bronchoconstriction commonly observed in asthma or COPD is not only a symptom but serves as an important factor of the diseases’ pathogenesis. Mechanical deformation of the airways occurring during the episodes of bronchoconstriction or accompanying chronic airflow limitation may per se promote respiratory inflammation and remodeling, thus, forming a vicious cycle. The precise molecular mechanisms triggering the response to mechanical stress in the airways have not been established so far. In this regard, a particular attention is drawn to TRP channels – polymodal receptors sensitive to many physical and chemical stimuli including stretching and compression at cellular level. TRPV4 is a mechanosensitive channel abundantly expressed in the airway epithelium that was previously proved to participate in stretch-induced respiratory responses during mechanical ventilation. The aim of this study was to establish the effects of SNPs located in TRPV4 region on the airway response induced by inspiratory resistive breathing. The study enrolled 122 patients with asthma, 82 patients with COPD and 54 healthy subjects. All the participants underwent 5-min isocapnic (5% CO2) inspiratory resistive breathing with load at 45% of maximum inspiratory pressure. Specific airway conductance (sGaw) was measured by body plethysmography before and after the inspiratory load. Relative change (Δ) in sGaw by ≥20% was considered as a significant response. Six SNPs (rs7139451, rs11068434, rs3825394, rs3825396, rs6606743, rs3742034) were genotyped by LATE-PCR with melting analysis of molecular beacon probes. All the studied SNPs were in Hardy-Weinberg equilibrium. SNP rs3825396 located in intronic region of TRPV4 exerted significant effect on the airway response to mechanical stress. In general sample, carriers of the AG genotype had higher ΔsGaw (9.0 (-8.5-30.6)%) in comparison with the GG homozygotes (-6.4 (-20.0-11.9)%, p=0.01). This trend was evident in the subgroups of healthy subjects, asthma and COPD patients, although the difference was not significant due to reduced number of observations. Carriers of the AA genotype were absent both in our sample and in reference HapMap population. The AG genotype was found in 5.4%, 13.3% and 25.0% of subjects with ΔsGaw ≤-20%, -20%<ΔsGaw<20% and ΔsGaw ≥20%, respectively (p=0.01). The difference was even more significant when comparing only between cases with ΔsGaw ≥20% and ΔsGaw ≤-20% (p=0.007). This association retained after adjustment for sex, age and diagnosis in logistic regression model (adjusted OR 5.2 95%CI (1.3-20.6), p=0.02). We did not found significant associations with the airway response to mechanical stress for the other studied SNPs. In conclusion, we established that TRPV4 rs3825396 SNP may influence reaction of the respiratory tract to increased inspiratory load. This association seems to be independent of the presence of the obstructive airway pathology, although further verification on larger sample is required.