Interstitial lung diseases (ILD) include a wide range of diseases impacting lung parenchyma and leading to fibrosis and architectural distortion. Chronic cough and dyspnea are common symptoms which affect the quality of life (QoL) in ILD patients. The mechanisms of cough in ILD patients are still unknown. The aim of this study was to prospectively investigate histological, radiological, and physiological determinants of cough-related QoL in ILD patients who underwent transbronchial lung cryobiopsy (TBLC). All patients (n = 111) filled in The Leicester Cough Questionnaire (LCQ) and The St George's Respiratory Questionnaire (SGRQ). They underwent lung function tests, forced vital capacity (FVC), forced vital expiratory volume in 1s (FEV1), diffusion capacity to carbon monoxide (DLCO), high-resolution computed tomography (HRCT), and blood samples before diagnostic TBLC. Two experienced radiologists assessed the extents of following HRCT patterns: ground-glass opacities (GGO), honeycombing, reticulation, traction bronchiectasis, and emphysema. Histology of TBLC were re-analyzed by two experienced pulmonary pathologists and the presence of fibroblast foci, fibrosis, giant cells, granulomas, and honeycombing were recorded. In the median multivariate regression analysis, BMI (-0.19; 95% CI -0.37- -0.014; p 0.035), GGO (-0.38; 95% CI -0.61- -0.15; p 0.001), granulomas (-3.21; 95% CI -6.12- -0.30; p 0.031), and current smoking (2.49; 95% CI 0.12-4.86; p 0.040) showed independent associations with LCQ total score. BMI (1.3; 95% CI 0.20-2.42; p 0.021) and DLCO (-0.51; 95% CI -0.85 - -0.16; p 0.004) showed independent association with SGRQ total score. Determinants of cough-related QoL in ILD patients are multifactorial including physiological, radiological and histological parameters.