The aim of this study was to develop and assess the validity and reliability of disease-specific oral health-related quality of life (OHRQoL) instrument for oral submucous fibrosis (OSF). Items for the OHRQoL-OSF were generated from personal interviews and focus group discussions, the existing questionnaires, reviews of literature and inputs from expert's panel. Item reduction was performed by clinical impact method followed by pretesting of the developed questionnaire. The validity and reliability of the instrument were then examined. Forty-five items were generated from qualitative data and item pooling from various sources. After item reduction, 17 items were finalized with four domain-structure having Eigenvalues greater than 1. OHRQoL-OSF was shown to be valid in distinguishing patients with varying degrees of OSF severity. For the concurrent validity, the observed impact of OSF based on OHRQoL-OSF significantly correlated with Oral Health Impact Profile and global self-ratings of oral health and overall well-being. OHRQoL-OSF and all its domains demonstrated good internal consistency reliability with Cronbach's alpha ˃0.7 and excellent test-retest reliability (ICC=0.96). The first disease-specific OHRQoL-OSF instrument appeared to be highly reliable and valid measure for assessing impact of OSF on life quality.