This analysis compared medication attitudes and reasons for nonadherence in three distinct groups of patients with serious mental illness (SMI). Cohort 1 had 43 patients with bipolar disorder (BD) treated in a community mental health setting, cohort 2 had 43 patients with BD taking an atypical antipsychotic and treated in an academic medical center, and cohort 3 had 30 patients with schizophrenia or schizoaffective disorder who had been homeless in the last year. Standardized attitudinal scales found generally negative attitudes toward medication and limited illness insight. Although the three cohorts differed with regard to severity of symptoms, age of onset, education, baseline adherence, and race, the groups had similar medication attitudes before and after treatment. Despite group differences in demographic and clinical variables, our analyses found more similarities than differences in medication attitudes among these three discrete groups of poorly adherent, symptomatic patients with SMI. The common attitudinal characteristics have implications for delivery of health care services that can enhance treatment adherence in high-risk SMI patients.