Long-haul truck driving has been associated with HIV risk in developing countries but little research to date has considered whether truckers in the USA may also be at elevated risk for HIV and other STIs. This multi-method qualitative study explored HIV-risk factors among regional and cross-country truck drivers who were based in the southeastern USA. Data collection methods included focus groups conducted at company hubs and over Citizen's Band (CB) radio, and key informant interviews. Results indicated that sexual opportunities and risks are greater for long-haul drivers who often travel for long periods without returning home and who may engage in 'highway sex' in the absence of a regular home-life. Structural factors that have reduced drivers' autonomy, sexual risk taking and free time while traveling include recent trucking regulations, electronic surveillance and industry-wide trends emphasizing speed and efficiency. Other factors, such as age, experience, type of employment and type of route also play a role. Further research is needed to determine if these qualitative findings can be quantified in population-based studies that also include biomarker and incidence data.