Objective This study aimed to examine levels of depression and quality of life in Spanish-speaking (less acculturated) immigrants with epilepsy compared with those in English-speaking US-born persons with epilepsy (PWEs). Methods The study included 85 PWEs — 38 Spanish-speaking immigrants with epilepsy and 47 US-born PWEs. All patients underwent video-EEG monitoring and completed depression and quality-of-life inventories in their dominant language (Spanish/English). Chart review of clinical epilepsy variables was conducted by an epileptologist. Results Our study revealed that depression scores were significantly higher in Hispanic PWEs (21.65±14.6) than in US-born PWEs (14.50±10.2) (t (64.02)=−2.3, two-sided p=.025). Marital status, medical insurance, antidepressant use, seizure frequency, and number of antiepileptic drugs (AEDs) were tested as covariates in the ANCOVA framework and were not statistically significant at the 0.05 significance level. Fewer Hispanics were prescribed antidepressant medications (13.15% for Hispanics and 40.42% for US-born, χ2 (1,85) 7.71, p=.005) and had access to comprehensive health insurance coverage (χ2 (1,85)=13.70, p=0.000). Hispanic patients were also found to be receiving significantly less AEDs compared with their US-born peers (t (83, 85)=2.33, p=.02). Although quality of life was diminished in both groups, Seizure Worry was worse for Hispanics after accounting for potential effects of marital status, medical insurance, use of antidepressants, seizure frequency, and number of antiepileptic drugs (AEDs) ((1, 83), F=7.607, p=0.007). Significance The present study is the first of its kind to examine depression and quality of life in Spanish-speaking US immigrants with epilepsy. Spanish-speaking immigrants with epilepsy have been identified as a group at risk. They demonstrated higher depression scores and more Seizure Worry independent of epilepsy and demographic characteristics compared with their US-born peers. The Hispanic group was receiving less treatment for depression, was taking less AEDs, and had less access to comprehensive health coverage compared with non-Hispanics.