Abstract Background The purpose of this research was to replicate a successful intervention to increase physical activity in a different region of the country, and explore genetic and physiological moderators of intervention efficacy drawn from a transdisciplinary theoretical framework. Method A randomized controlled trial comparing a print-based physical activity intervention (COSTRIDE) to a print-based health and wellness contact control (HW) intervention was conducted. Sedentary participants (n = 219) completed assessments at baseline and follow-up assessments at 3, 6, 9, and 12 months following the initiation of the intervention. Results Participants in both conditions significantly increased exercise behavior in the first six months, and then leveled off or decreased physical activity in the second six months of the study. Those in the COSTRIDE intervention increased significantly more than those in the HW intervention, and were better able to maintain their exercise behavior. Genetic factors (BDNF, rs6265; FTO, rs8044769), but not selected physiological (body temperature, blood lactate, systolic blood pressure, plasma norepinephrine, and heart rate) or subjective (perceived pain, affect) responses to physical activity, moderated response to the intervention. Conclusions There are underlying genetic factors that influence response to behavioral intervention, and a better understanding of these factors has the potential to influence the development, targeting and tailoring of behavioral interventions to increase physical activity. Trial registration Clinicaltrials.gov registration: NCT01091857.