PURPOSE: To compare the neurotrophic factor response following one session of high-intensity exercise, resistance training or both in a cohort of physically inactive overweight adults aged 18-30 years old. METHODS: A randomized, parallel-group clinical trial of fifty-one men (23.6±3.5 years; 83.5±7.8 kg; 28.0±1.9 kg/m2) who are physically inactive (i.e., <150 min of moderate-intensity exercise per week for greater than 6 months) and are either abdominally obese (waist circumference ≥ 90 cm) or have a body mass index ≥ 25 and ≤ 30 kg/ m2 were randomized to the following four exercise protocols: high-intensity exercise (4×4 min intervals at 85-95% maximum heart rate [HRmax] interspersed with 4 min of recovery at 75-85% HRmax) (n=14), progressive resistance training (25 to 30 repetitions per set, at 70% of one repetition maximum with 60 s of recovery) (n=12), combined high-intensity and resistance exercise (n=13), or non-exercising control (n=12). The plasma levels of neurotrophin-3 (NT-3), neurotrophin-4 (also known as neurotrophin 4/5; NT-4 or NT-4/5), and brain-derived neurotrophic factor (BDNF) were determined before (pre-exercise) and 1-min post-exercise for each protocol session. RESULTS: Resistance training induced trivial increases in BDNF, NT-3 and NT-4/5 (15.5 ng/mL [95% CI, 1.2 to 32.3; d=0.14], 39.6 ng/mL [95% CI, 2.5 to 76.6; d=0.19], and 1.3 ng/mL [95% CI, 0.3 to 2.3; d=0.17], respectively). Additionally, combined training results in favorable effects on both BDNF (22.0, 95% CI, 2.6 to 41.5; d=0.19) and NT-3 (32.9, 95% CI, 12.4 to 53.4; d=0.25). In the per-protocol analyses, the combined training group but not the other interventions showed greater changes in BDNF (99.7, 95% CI, 22.4 to 176.7; d=1.01), NT-3 (89.9, 95% CI, 2.2 to 172.1; d=0.79), and NT-4 (7.5, 95% CI, 1.7 to 13.3; d=1.07) compared to the control group. CONCLUSIONS: The findings indicate that acute resistance training and combined exercise increase neurotrophic factors in physically inactive overweight adults. Further studies are required to determine the biological importance of changes in neurotrophic responses in overweight men and chronic effects of these exercise protocols.