Substance use is common in first-episode psychosis (FEP) and has been linked to poorer outcomes with more severe psychopathology and higher relapse rates. Early substance discontinuation appears to improve symptoms and function. However, studies vary widely in their methodology, and few have examined patients longitudinally, making it difficult to draw conclusions for practice and treatment. We aimed to investigate the relationship between substance use and early abstinence and the long-term course of illness in a representative sample of FEP patients. Out of 301 included patients, 266 could be divided into 4 groups based on substance use patterns during the first 2 years of treatment: persistent users, episodic users, stop-users and nonusers. Differences in clinical and functional measures during the follow-up period were assessed using linear mixed effects models for the analysis of repeated measures data. Patients who stopped using substances within the first 2 years after diagnosis had outcomes similar to those who had never used with fewer symptoms than episodic or persistent users. Both episodic and persistent users had lower rates of symptom remission than nonusers, and persistent users also had more negative symptoms than those who stopped using. Our findings emerge from one of very few long-term longitudinal studies examining substance use cessation in FEP with 10-year follow-up. The results convey hope that the detrimental effects of substance abuse on mental health may be significantly reversed if one stops the abuse in time. This can help patients who struggle with addiction with their motivation to embrace abstinence.