The preponderance of evidence from large-scale studies shows a detrimental association between greater acculturation (to mainstream U.S. values and beliefs) and mental health. Prior research also suggests that greater acculturation may be associated with a breakdown of adaptive behaviors and values (e.g., religiosity/spirituality) thereby negatively impacting mental health. In addition, literature generally suggests that enculturation (retention of culture of origin customs and values) is associated with better mental health. However, few studies have examined potential mediators between acculturation/enculturation and mental health; and research on this topic with patients with schizophrenia is particularly scarce. Using a sample of 44 Hispanic and African-American patients with schizophrenia, this study evaluated whether higher acculturation and lower enculturation would be associated with more symptoms of schizophrenia. Religiosity/spirituality, family cohesion, and religious coping were evaluated as potential mediators of these relationships. As hypothesized, greater family cohesion (measured by the Family Environment Scale) was associated with fewer schizophrenia symptoms (measured by the Brief Psychiatric Rating Scale). However a meditational model was not supported. Contrary to hypotheses, when examining the total sample, neither acculturation nor enculturation (measured by the Abbreviated Multidimensional Acculturation Scale) were associated with schizophrenia symptoms. Ethnic subgroup analyses were conducted and will be discussed along with study implications, limitations, and directions for future research.