This study aimed to explore patient-, provider-, and system-level factors that may contribute to elevated risk of patient safety events among persons with serious mental illness (SMI). We conducted a medical record review of medical/surgical admissions in Maryland hospitals from 1994 to 2004 for a community-based sample of adults with SMI (N = 790 hospitalizations). We estimated the prevalence of multiple patient, provider, and system factors that could influence patient safety among persons with SMI. We conducted a case crossover analysis to examine the relationship between these factors and adverse patient safety events. Patients' mental status, level of consciousness, disease severity, and providers' lack of patient monitoring, delay/failure to seek consultation, lack of trainee supervision, and delays in care were positively associated with adverse patient safety events (p < 0.05). Efforts to reduce SMI-related patient safety risks will need to be multifaceted and address both patient- and provider-level factors.