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Background: Hispanic/Latinx smokers living in the United States face unique challenges in quitting smoking. This study evaluated the efficacy of a culturally relevant, Spanish‐language, extended self‐help smoking cessation intervention among Hispanic smokers. Methods: A 2‐arm parallel randomized controlled trial was conducted with Hispanic/Latinx smokers living in the United States who preferred health information in Spanish and smoked 5 or more cigarettes per week. Participants were randomly allocated to receive Libre del Cigarrillo (LDC), which consisted of 11 booklets and 9 pamphlets mailed monthly over 18 months, or the usual care (UC), which was a single Spanish‐language self‐help booklet from the National Cancer Institute. The primary outcome was self‐reported 7‐day point prevalence smoking abstinence assessed 6, 12, 18, and 24 months after the baseline. Eight prespecified moderators of the intervention were evaluated. Cost‐effectiveness was also evaluated. All statistical tests were 2‐sided. Results: Data from all participants randomized to LDC (n = 714) or UC (n = 703) were used for analyses after multiple imputation to manage missing data. Generalized estimating equation analyses indicated that LDC abstinence rates were higher (P <.001) across all assessments. Logistic regression analyses revealed that at 24 months, the abstinence rate was greater for LDC (33.1%) than UC (24.3%; odds ratio, 1.54; 95% confidence interval, 1.18‐2.02; P =.002). Men exhibited a strong intervention effect at all assessments (P values <.001), whereas the intervention effect for women was observed only at 6 and 12 months (P values <.018). In comparison with UC, the incremental cost per quitter in the LDC arm was $648.43 at 18 months and $683.93 at 24 months. Conclusions: A culturally relevant, Spanish‐language intervention was efficacious and cost‐effective for smoking cessation. Lay Summary: Research is needed to develop interventions for ethnic minority smokers.The aim of the current study was to test a Spanish‐language adaptation of a validated and easily implemented self‐help smoking cessation intervention in a nationwide randomized controlled trial.The findings demonstrated that the intervention produced greater smoking abstinence in comparison with a standard self‐help booklet.Participants also were more satisfied with the intervention, and it was cost‐effective.Efforts aimed at promoting tobacco abstinence in this underserved population could have significant public health implications, including potential reductions in cancer health disparities associated with tobacco smoking. This large, nationwide randomized controlled trial demonstrates that a culturally relevant, Spanish‐language, extended self‐help intervention is efficacious and cost‐effective for smoking cessation, and it supports the tailoring of interventions to Hispanics by identifying and integrating cultural values. The evaluated intervention approach has potential for broad dissemination and reach to reduce cigarette smoking and has implications for cancer prevention because smoking is the primary risk factor for lung cancer, which is the leading cause of cancer death among Hispanic men and is second only to breast cancer among Hispanic women. [ABSTRACT FROM AUTHOR]