The Latino population is now the largest minority group in the United States (US). The higher prevalence of obesity among Mexican immigrants and Mexican-Americans (MI-MA) living in the US compared with Non-Hispanic Whites has been linked to socio-demographic and behavioral factors. There is emerging evidence that suggests features of the social environment and neighborhood socio-economic characteristics may have an influence on Latinos' obesity rates. This study was guided by the social-ecological model and used multilevel analytic methods to examine macro, meso and cultural exchange level factors associated with obesity among MI-MA living in the border region of San Diego, CA. Data were collected as part of the San Diego Prevention Research Center Community Survey. Multistage sampling methods were used to recruit participants into the study. Multilevel models were conducted to examine the association of these factors at multiple social-ecological levels on obesity. Three hundred and ninety seven people completed the survey. The mean age of respondents was 43.4 ± 16.9, 72.6% were females and 77% were born in Mexico. Respondents scored high in the Hispanic domain of acculturation and crossed the border about three times per month mostly to visit family and friends in Mexico. Collective efficacy was an average of 3.5 (range 1 to 5). Respondents reported having 4 (0-5) people in their social network with an average reciprocity of 15 times per month. Neighborhoods where respondents live were on average 68% Latino with 27% of home ownership. Almost forty seven percent of respondents were obese. After controlling for micro-level characteristics, health behaviors and neighborhood clustering, the final model suggested that respondents who were employed, with an income below the poverty threshold were less likely to be obese. Middle-aged respondents with larger social networks were more likely to be obese. Two cross-level interactions were significantly associated with obesity. Times crossing the border to Mexico in the last month moderated the effect of collective efficacy on obesity. Neighborhood percentage of home ownership moderated the association between Hispanic domain and obesity. The study provided evidence that the meso, macro and cultural exchange level factors are associated with obesity among MI-MA living in this border region. This study provides the foundation to further investigate the influence of higher social-ecological level determinants of health among MI-MA living in this unique place of influence, the Southern California, US-Mexico border.