Background: Persons with schizophrenia patient and misusing methamphetamines suffering from social dysfunction that impact on their quality of life. Knowledge of factors related to social dysfunction will guide the effective intervention. Objectives: To determine the direct effect, indirect effect and total effect of an acerbate Psychotics’ Symptoms, Social Support, Stressful life events, Medication use self-efficacy impact on social dysfunction in Thai schizophrenic patient and methamphetamine misuse. Methods: Data were collected from schizophrenic and methamphetamine misuse patient by self report. A linear structural relationship was used to test the hypothesized path model. Results: The hypothesized model was found to fit the empirical data and explained 54% of the variance of the psychotic symptoms (X2 = 114.35, df = 92, p-value = 0.05, X2 /df = 1.24, GFI = 0.96, AGFI = 0.92, CFI = 1.00, NFI = 0.99, NNFI = 0.99, RMSEA = 0.02). The highest total effect on social dysfunction was psychotic symptoms (0.67, p<0.05). Medication use self-efficacy had a direct effect on psychotic symptoms (-0.25, p<0.01), and social support had direct effect on medication use self efficacy (0.36, p <0.01). Conclusions: Psychotic symptoms and stressful life events were the significance factors that influenced direct on social dysfunctioning. Therefore, interventions that are designed to manage these factors are crucial in order to enhance social functioning in this population.