Background Evidence suggests immigrant Latinos are at decreased risk of psychiatric disorders but subgroup differences are often ignored. The present study evaluates the relationship between English language proficiency, discrimination, acculturative stress, and family conflict and past-year psychiatric disorder by generational status, which affects the life stages during which individuals are exposed to U.S. culture. Methods This study uses cross-sectional data on 2,554 Latinos from the National Latino and Asian American Survey. Chi-square tests assessed generational differences in acculturative experiences and past-year prevalence of DSM-IV depressive(DD), anxiety(AD), and substance use disorders(SUD). Logistic regression estimated relative odds of disorder, stratified by generational status. Results English proficiency, discrimination, acculturative stress and family conflict differed significantly by generational status (all p<0.0001). First-generation respondents had lower English proficiency(18.2%) than other groups(range:81.9%-92.8%,X2=1292), but experienced less discrimination(54.9% vs. 74.2%-84.6%,X2=173) and family conflict(40.7% vs. 53.7%-57.9%,X2=58.7). SUD prevalence was higher among U.S.-born respondents(5.2% vs. 1.0% of foreign-born,X2=41.7,p<0.0001). First-generation Latinos speaking good/excellent English were more likely to have past-year SUD(OR=14.1,95%CI:1.47-135.0) than non-English-speakers. Discrimination increased odds of past-year DD among generation 1.5 Latinos(OR=12.6,95%CI:1.6-97.1) and AD in the 1.5 (OR=14.6,95%CI:1.9-110.0) and second generations(OR=3.0,95%CI:1.1-7.9). Acculturative stress was associated with past-year DD for foreign-born groups(first generation OR=1.7,95%CI:1.1-2.6; 1.5 generation OR=3.0,95%CI:1.0-8.9) and past-year AD for first-generation immigrants(OR=1.9,95%CI:1.3-2.9). Family conflict increased odds of all disorders for first and second-generation Latinos, especially SUD(OR=10.2,95%CI:1.3-82.6; and OR=6.0,95%CI:1.8-20.5, respectively). Conclusions Acculturative experiences and their relationship to psychiatric disorders vary across Latino generational subgroups. Future research should account for generational heterogeneity when identifying modifiable risk factors for disorders among U.S. Latinos.