OBJECTIVE: This study investigated cross-sectional and longitudinal associations of fast-food outlet exposure with BMI and BMI change, as well as moderation by age and genetic predisposition. METHODS: This study used Lifelines' baseline (n = 141,973) and 4-year follow-up (n = 103,050) data. Participant residential addresses were linked to a register with fast-food outlet locations (Nationwide Information System of Workplaces [Dutch: Landelijk Informatiesysteem van Arbeidsplaatsen, LISA]) using geocoding, and the number of fast-food outlets within 1 km was computed. BMI was measured objectively. A weighted BMI genetic risk score was computed, representing overall genetic predisposition toward elevated BMI, based on 941 single-nucleotide polymorphisms genome-wide significantly associated with BMI for a subsample with genetic data (BMI: n = 44,996; BMI change: n = 36,684). Multivariable multilevel linear regression analyses and exposure-moderator interactions were tested. RESULTS: Participants with ≥1 fast-food outlet within 1 km had a higher BMI (B [95% CI]: 0.17 [0.09 to 0.25]), and those with ≥2 fast-food outlets within 1 km increased more in BMI (B [95% CI]: 0.06 [0.02 to 0.09]) than participants with no fast-food outlets within 1 km. Effect sizes on baseline BMI were largest among young adults (age 18-29 years; B [95% CI]: 0.35 [0.10 to 0.59]) and especially young adults with a medium (B [95% CI]: 0.57 [-0.02 to 1.16]) or high genetic risk score (B [95% CI]: 0.46 [-0.24 to 1.16]). CONCLUSIONS: Fast-food outlet exposure was identified as a potentially important determinant of BMI and BMI change. Young adults, especially those with a medium or high genetic predisposition, had a higher BMI when exposed to fast-food outlets.