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Abstract Prostate cancer (PCa) is the most common invasive malignancy for men in the USA. The incidence and mortality rates of PCa are significantly higher among African American men, as compared to those in Caucasian men. Betulinic acid (BA) is a penta-cyclic triterpenoid that is often found in the bark of several species of plants. It possesses a variety of biological activities, including anti-cancer activities. We examined the cytotoxic effects and endoplasmic reticulum (ER) stress induced by BA and its ionic derivatives with PCa cells derived from African Americans and Caucasian men. The viability of all PCa cells was reduced by the BA compounds, and the cytotoxicity of these BA compounds was independent of ethnicity and androgen dependency. The BA compounds induced modest effects on ER stress proteins when compared with ER stress inducers, tunicamycin and thapsigargin. The induction of glucose regulated protein 78 (GRP78) was largely correlated with the expression of C/EBP homologous protein (CHOP) and cleaved poly [ADP-ribose] polymerase (PARP)/caspase-3 in the PCa cells. In summary, our data demonstrated that BA compounds impaired the growth of PCa cells regardless of ethnicity – through GRP78- and CHOP-independent pathways.