Background: Although studies have shown a cross-sectional link between discrimination and smoking, the prospective influence of discrimination on smoking cessation has yet to be evaluated. Thus, the purpose of the current study was to determine the influence of everyday and major discrimination on smoking cessation among Latinos making a quit attempt. Methods: Participants were 190 Spanish speaking smokers of Mexican Heritage recruited from the Houston, TX metropolitan area who participated in the study between 2009 and 2012. Logistic regression analyses were conducted to evaluate the associations of everyday and major discrimination with smoking abstinence at 26 weeks post-quit. Results: Most participants reported at least some everyday discrimination (64.4%), and at least one major discrimination event (56%) in their lifetimes. Race/ethnicity/nationality was the most commonly perceived reason for both everyday and major discrimination. Everyday discrimination was not associated with post-quit smoking status. However, experiencing a greater number of major discrimination events was associated with a reduced likelihood of achieving 7-day point prevalence smoking abstinence, OR = .51, p = .004, and continuous smoking abstinence, OR = .29, p = .018, at 26 weeks post-quit. Conclusions: Findings highlight the high frequency of exposure to discrimination among Latinos, and demonstrate the negative impact of major discrimination events on a smoking cessation attempt. Efforts are needed to attenuate the detrimental effects of major discrimination events on smoking cessation outcomes.