BACKGROUND: American Indian (AI) and Alaska Native (AN) communities experience disproportionately high rates of tobacco use when compared to the overall U.S. population, especially among rural populations. METHODS: We implemented a single-blind, randomized clinical trial of a text messaging-based smoking cessation intervention through the tobacco quitlines of five states (Alaska, Minnesota, New Mexico, Oklahoma, and Wisconsin) with high percentages of AI residents. We partnered with state quitlines and Optum, a multi-state entity that manages quitlines. Participants who called the quitlines and identified as AI/AN were given the option to enroll in this trial. Upon consent, they were randomly assigned to either the standard quitline program (control) or a program culturally tailored for AI/ANs (intervention), which used a text messaging intervention to encourage smoking cessation. We adapted the text messages based on key informant and focus group input. Baseline data was analyzed for differences across age, sex, and the Fagerström Test for Nicotine Dependence. RESULTS: We recruited n = 487 AIs into the trial. Participants had an average age of 41.9 years (SD = 11.7) and 66% were female. The average Fagerström Test for Nicotine Dependence score was 5.38 (SD = 2.37). The intervention and control arms did not significantly differ across any of the baseline characteristics. CONCLUSION: Implementation of this trial illustrated important lessons in adapting, implementing, and evaluating trials in collaboration with AI communities and local and national organizations. This work will inform future efforts to implement culturally-tailored interventions with AI/ANs and advance our knowledge about adapting and implementing smoking cessation interventions.