Custom made foot orthoses (CFO) with specific material properties have the potential to alter ground reaction forces but their effect on running mechanics and comfort remains to be investigated. We determined if CFO manufactured from ethyl-vinyl acetate (EVA) and expanded thermoplastic polyurethane (TPU) materials, both compared to standardized footwear (CON), improve running economy (RE), running mechanics, and comfort at two running speeds. Eighteen well-trained, male athletes ran on an instrumented treadmill for 6 min at high (HS) and low (LS) speeds corresponding to and 15% lower than their first ventilatory threshold (13.8 ± 1.1 and 11.7 ± 0.9 km.h −1 , respectively) in three footwear conditions (CON, EVA, and TPU). RE, running mechanics and comfort were determined. Albeit not reaching statistical significance (P = 0.11, η 2 = 0.12), RE on average improved in EVA (+2.1 ± 4.8 and +2.9 ± 4.9%) and TPU (+0.9 ± 5.9 and +0.9 ± 5.3%) compared to CON at LS and HS, respectively. Braking force was decreased by 3.4 ± 9.1% at LS and by 2.7 ± 9.8% at HS for EVA compared to CON (P = 0.03, η 2 = 0.20). TPU increased propulsive loading rate by 20.2 ± 24 and 16.4 ± 23.1% for LS and HS, respectively compared to CON (P = 0.01, η 2 = 0.25). Both arch height (P = 0.06, η 2 = 0.19) and medio-lateral control (P = 0.06, η 2 = 0.16) showed a trend toward improved comfort for EVA and TPU vs. CON. Compared to shoes only, mainly EVA tended to improve RE and comfort at submaximal running speeds. Specific CFO-related running mechanical adjustments included a reduced braking impulse occurring in the first 25% of contact time with EVA, whereas wearing TPU increased propulsive loading rate.