BACKGROUND It has been hypothesized that smoking is associated with the severity of negative symptoms. Until now, no studies have investigated whether the impact of smoking on negative symptoms is dependent on antioxidants. This study was designed to evaluate the effect of smoking on therapeutic response and total antioxidants capacity (TAOC) in antipsychotic-naïve first-episode (ANFE) patients. METHODS The severity of the patient's symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). A total of 237 ANFE patients were recruited and treated with risperidone (oral tablets, 4-6 mg/day twice a day) for 12 weeks. PANSS was assessed at baseline and a 12-week follow-up. Plasma TAOC levels were also assayed at baseline and week 12. RESULTS Relative to nonsmokers with ANFE SZ, smokers had higher PANSS negative subscores. There was no significant difference in TAOC changes after 12 weeks of treatment with risperidone between smokers and non-smokers. However, we found greater improvement in negative symptoms in smokers compared to non-smokers. Further analysis in smokers with SZ demonstrated that improvements in negative symptoms were not associated with changes in TAOC. CONCLUSIONS Our study suggested that smoking affected the severity of baseline negative symptoms and further contributed to their reduction after risperidone treatment. However, improvement in negative symptoms was not dependent on the changes in TAOC.