We 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 4days separated by ∼1week. One hour before TT, participants ingested either caffeine (3mgkgbw-1) or placebo pills, after which femoral blood-flow was either restricted with occlusion cuffs inflated to ∼180mmHg (IPC), or sham-restricted (0-10mmHg; 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±17W in Placebo+Sham and not different from Placebo+IPC (-1W; 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 (+8W; 95% CI: 2-13; p=0.019; d: 0.79) versus Placebo+Sham. MPO differences were attributed to caffeine (caffeine main-effect: +7W; 95% CI: 2-13; p=0.015; d: 0.54. IPC main-effect: 0W; 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.