Objective. This study compared psychiatric diagnoses ascertained by independent clinicians with structured research interviews of homeless psychiatric patients assessed in a mental health clinic and in the community. Problems of both overdiagnosis and underdiagnosis in structured research interviews compared to clinician assessment were predicted. Method. Over a period of a year, 97 patients referred to a mental health clinic for homeless people were assessed with the Diagnostic Interview Schedule (DIS) administered by a clinical social worker who then completed a full clinical psychiatric social work assessment. These same patients received a thorough and systematic clinical psychiatric evaluation by a psychiatrist or psychologist, both experienced with this population. These clinicians gathered data from multiple sources, often with extended observation over time. The DIS and clinician diagnoses were made blind to one another and then compared; the clinician was often made aware of some of the symptoms that the social worker had elicited, but not whether the elicited material was from the DIS or from the clinical assessment. Diagnoses of 33 clinic patients previously assessed by trained nonclinician DIS interviews in an epidemiologic study of the homeless population in the community were also compared to clinician diagnoses, and no information from these patients' survey DIS interviews was made available to the clinicians. Results. Compared to clinician assessment, structured interviews underdiagnosed antisocial personality disorder (ASPD) and overdiagnosed major depression. Alcohol use disorder and schizophrenia showed only small discrepancies by assessment method. Drug use disorder revealed no bias according to method of ascertainment, but showed very discrepant kappa levels comparing DIS to clinician assessment in the two different comparison contexts. Conclusions. If structured research methods assessing the homeless population actually overestimate depression, underestimate ASPD, and misclassify drug abuse, then policies stemming from structured interview research recommendations may call for levels and types of services not optimally suited to the reality of this population's needs. Because mental illness and substance abuse are thought to be critical factors in the generation and perpetuation of homelessness, the issue of accurate diagnosis is tantamount to understanding and providing workable solutions to the problem of homelessness. Further research is needed to untangle potential confounders of the homeless situation to psychiatric diagnosis.