TB treatment interruption has resulted in delayed sputum conversion, drug resistance, and a high mortality rate and a prolonged treatment course, hence leading to economic and psychosocial affliction. To date, there are limited studies investigating the physico-social risk factors for early treatment interruptions. This prospective multicenter cohort study aimed to investigate the risk factors for early treatment interruption among new pulmonary tuberculosis (TB) smear-positive patients in Selangor, Malaysia. A total of 439 participants were recruited from 39 public treatment centres, 2018-2019. Multivariate Cox proportional hazard analyses were performed to analyse the risk factors for early treatment interruption. Of 439 participants, 104 (23.7%) had early treatment interruption, with 67.3% of early treatment interruption occurring in the first month of treatment. Being a current smoker and having a history of hospitalization, internalized stigma, low TB symptoms score, and waiting time spent at Directly Observed Treatment, Short-course centre were risk factors for early treatment interruption. An appropriate treatment adherence strategy is suggested to prioritize the high-risk group with high early treatment interruption. Efforts to quit smoking cessation programs and to promote stigma reduction interventions are crucial to reduce the probability of early treatment interruption.