The capsaicin receptor (TRPV1) antagonist ABT-102 demonstrates efficacy in multiple preclinical pain models. However, evolving clinical data for this compound class suggest potentially profound drug-induced thermosensory impairment. Safety and tolerability of ABT-102 were assessed in a multiple-dose, double-blind, placebo-controlled, randomized healthy volunteer trial. Thirty-six participants were randomized in a 2:1 ratio to ABT-102:placebo in 3 dose groups (1 mg, 2 mg, and 4 mg twice a day) and confined to an inpatient research unit for a 7-day treatment period and 3 follow-up days. Outcome measures included: oral and cutaneous cold detection, warm detection (WDT), and heat pain thresholds (HPT); oral perceived heat intensity (oral liquid test); time to hand withdrawal (water bath test); and cutaneous pain intensity (long thermal stimulus). Significant dose-dependent (placebo- and baseline-adjusted) increases in HPT and reduced painfulness of suprathreshold heat were present from days 1–7. For ABT-102 4 mg twice a day, model-based mean differences from placebo (95% confidence interval) were as follows: oral HPT, day 1 = 2.5°C (0.6–4.4), day 5 = 4.4°C (2.5–6.3); cutaneous HPT, day 2 = 3.3°C (1.4–5.3), day 5 = 5.3°C (3.3–7.2); oral WDT, day 1 = 2.6°C (0.5–4.7), day 5 = 2.7°C (0.6–4.9); cutaneous WDT, day 2 = 1.3 (0.0–2.6), day 5 = 1.6 (0.3–2.8) (all P < 0.05). Oral liquid test and water bath test results followed a similar pattern. There was no effect on cutaneous cold detection. All effects were fully reversed by day 10. There were no other relevant safety findings. Core body temperature remained below 39°C in all participants. In conclusion, ABT-102 potently and reversibly increased HPT and reduced painfulness of suprathreshold oral/cutaneous heat. In a randomized, double-blind, placebo-controlled trial, the selective TRPV1 antagonist ABT-102 potently and reversibly increased heat pain threshold and reduced painfulness of suprathreshold oral/cutaneous heat.