AbstractWe investigated the effect of ischemic preconditioning (IPC) with and without caffeine supplementation on mean power output (MPO) during a 4‐min cycling time‐trial (TT). In a double‐blinded, randomized, crossover‐design, 11 trained men performed a TT on 4 days separated by ∼1 week. One hour before TT, participants ingested either caffeine (3 mg kg bw⁻¹) or placebo pills, after which femoral blood‐flow was either restricted with occlusion cuffs inflated to ∼180 mmHg (IPC), or sham‐restricted (0–10 mmHg; Sham) during 3 × 2‐min low‐intensity cycling (10% of incremental peak power output). Then, participants performed a standardized warm‐up followed by the TT. Plasma lactate and K⁺ concentrations and ratings of perceived exertion (RPE) were measured throughout trials. TT MPO was 382 ± 17 W in Placebo + Sham and not different from Placebo + IPC (−1 W; 95% CI: −9 to 7; p = 0.848; d: 0.06), whereas MPO was higher with Caffeine + Sham (+6W; 95% CI: −2 to 14; p = 0.115; d: 0.49) and Caffeine + IPC (+8 W; 95% CI: 2–13; p = 0.019; d: 0.79) versus Placebo + Sham. MPO differences were attributed to caffeine (caffeine main‐effect: +7 W; 95% CI: 2–13; p = 0.015; d: 0.54. IPC main‐effect: 0 W; 95% CI: −6 to 7; p = 0.891; d: 0.03; caffeine × IPC interaction‐effect: p = 0.580; d: 0.17). TT RPE and plasma variables were not different between treatments. In conlcusion, IPC with co‐ingestion of placebo does not improve short‐term high‐intensity performance in trained men versus a double‐placebo control (Placebo + Sham) and does not additively enhance performance with caffeine. These data do not support IPC as a useful strategy for athletes prior to competition but confirms caffeine's performance‐enhancing effect.