Introduction: Little epidemiological evidence exists on alcohol or other substance use and related problems along the U.S.-Mexico border, although the border has been the focus of recent media attention related to the escalating drug/violence "epidemic". The purpose of this study was to analyze the association of variables related to crossing the border (cross-border mobility) with three substance use outcomes reported for the last year: 1) heavy drinking (5 + drinks per day for men or 4 + for women), 2) alcohol use disorder (ADD), and 3) co-occurring heavy drinking and drug use (any use of illicit and/or non-medically prescribed drugs). Methods: Household surveys were conducted, using area probability sampling of 1565 Mexican-American residents, aged 18-65, living at the Texas-Mexico border in the metropolitan areas of Laredo and McAllen/Brownsville. Results: Among those 18-29, more frequent crossing of the border was significantly predictive of ADD (OR = 1.61, p < 0.01) and co-occurring heavy drinking and drug use (OR = 1.70, p < 0.01). Staying more than one full day was predictive of ADD (OR = 3.07, p < 0.001) and crossing to obtain over-the-counter or prescription drugs ("drug tourism") or for nightlife/drinking were predictive of heavy drinking (ORs = 4.14, p < 0.001; 3.92, p < 0.01, respectively), ADD (ORs = 7.56, p < 0.001; 7.68, p < 0.01, respectively) and co-occurring heavy drinking and drug use (ORs = 8.53, p < 0.01; 4.96, p < 0.01, respectively). Among those 30-65, staying more than a full day and crossing for pharmaceutical reasons were predictive of heavy drinking (OR = 2.54, p < 0.001; 2.61, p < 0.05, respectively) and co-occurring heavy drinking and drug use (OR = 331, p < 0.001; 4.86, p < 0.01, respectively), while none of the mobility variables were predictive of AUD in this age group. Conclusions: Cross-border mobility may play an important role in substance use and problems, especially among those 18-29. Findings also highlight the importance of "drug tourism" in substance use across the age spectrum. (C) 2015 Elsevier Ltd. All rights reserved.