To address at least in part health disparities in Hispanic populations, the NIDA Clinical Trials Network implemented the first multi-site randomized clinical trial of substance abuse treatment conducted entirely in Spanish. This trial was intended to evaluate the effectiveness of Motivational Enhancement Therapy in a diverse population of Hispanics. In the conduct of this trial, several barriers to the successful implementation of a Spanish-language multi-site trial had to be addressed, including the appropriate translation of assessment instruments, shortage of appropriately trained Spanish-speaking clinical staff, and barriers to recruitment and retention of this population. To encourage similar research, strategies are described that were developed by the study team to meet these challenges.