Objectives-Injection drug use (IDU) remains an actual risk variable in HIV infection in most ethnic populations and the association between actual risk and individual perception of HIV risk varies across studies and samples. This study aimed to examine the relationship between IDU and HIV risk perception among Mexican Americans residing in Rio Grande Valley, South Texas.Study Design-A cross-sectional study of IDU as a predictor of HIV risk perception.Methods-We assessed 275 participants (IDU = 11.9%, non-IDU = 88.1%) for the association between IDU and individual risk perception for HIV infections, as well as history of drug use and HIV risk perception using chi square statistic for independence and logistic regression model for the prevalence odds ratio.Results-There was no statistically significant difference between IDU and non-IDU with respect to the socio-demographic variables except for income and gender, P < 0.05. The results further indicated a statistically significant decreased HIV risk perception among injection drug users (IDUs) compared with non-IDUs, after adjustment for age, gender, sexual preference, history of drug use and marital status, prevalence odds ratio (POR), 0.26, 95% Confidence Interval (CI), 0.11-0.65. Likewise, history of drug use was associated with decreased HIV risk perception, POR, 0.44, 95% CI, 0.22-0.98.Conclusions-These results suggest an inverse correlation between actual risk for HIV infection such as IDU and HIV risk perception. Therefore, assessing HIV risk perception, which is a significant determinant of behavior change, is essential in reducing HIV infection prevalence in the targeted population.