Background: Risk of infections is elevated in patients with schizophrenia. Predicting their occurrence is essential, as infections in this group of patients are associated with prolonged hospital admission and increased mortality. The objective of the current investigation was to identify the potential risk factors of major infection after diagnosis with schizophrenia. Methods: This national prospective observational cohort study included 7788 people with schizophrenia born in Denmark between 1975 and 1990. Socio-demographic, psychiatric and health related data were obtained from Danish national registers. The Cox regression model was used for data analyses. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95%CIs) are presented. Results: The most significant risk factors associated with the development of major infections included young age, female gender, medical comorbidity and substance abuse. A history of treatment with antipsychotics preceding the diagnosis was negatively associated with such morbidity. Conclusion: This study reports several factors that might increase the risk of infections in individuals with schizophrenia. Early intervention towards infections should be considered in the subpopulation of schizophrenia patients who are at increased risk of infections.