The purpose of this paper was to (1) examine the rates of elevated depression symptoms among a sample of rural Federally Qualified Health Center (FQHC) patients with chronic disease and (2) determine if an inability to afford general prescription medications within the past 12 months is a significant predictor of depression symptoms among these patients. These data came from Project EDUCATE, an ongoing five-year study designed to be a large-scale, multifocal examination of the needs and experiences of rural FQHC patients with hypertension and/or diabetes. A total of 497 rural FQHC patients completed surveys (including a series of psychosocial questions, the Multigroup Ethnic Identity Measure and the Center for Epidemiologic Studies Depression scale) as part of phase one of the project; 438 of these with complete data are included in the current analytic sample. Results revealed that 53.0% of the sample screened positive for depression, and over half of those who screened positive reported not being able to afford their prescription medications at least once within the past 12 months (51.3% vs. 26.3% non-depressed). Further, even after controlling for age, ethnic identity attachment, sex, education level, employment status, income, insurance status, recent inability to afford needed medical care, hypertensive status, mental health diagnosis, and family history of mental illness, patients who could not afford to fill their prescriptions in the past 12 months were 2.6 times as likely to screen positive for depression (ORADJ = 2.476, p = 0.002) as those who could afford their medications. Overall, results of this study suggest that, among rural patients diagnosed with chronic disease, depressive symptomatology may be alarmingly high and an inability to afford medications may be an important risk factor for depression symptoms. These results highlight the need for increased attention to prescription medication affordability among rural patients with chronic disease in order to reduce the risk of comorbid depression.