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OBJECTIVE To examine the effects of a single administration of focused extracorporeal shock wave therapy on eccentric exercise-induced delayed-onset muscle soreness (DOMS). DESIGN Three-arm randomized controlled study. SETTING University research center. PARTICIPANTS Participants (N=46; 23 women) had a mean age of 29.0±3.0 years and a mean body mass index of 23.8±2.8kg/m2. INTERVENTIONS Participants were randomly allocated to verum- (energy flux density, .06-.09mJ/mm2; pulse ratio per point, 200) or sham-focused extracorporeal shock wave therapy (no energy) at 7 equidistant points along the biceps muscle or no intervention. MAIN OUTCOME MEASURES The primary outcome was the difference in pain intensity. Secondary outcomes included maximum isometric voluntary force (MIVF), pressure pain threshold (PPT), and impairment in daily life. RESULTS Despite descriptive clinically meaningful differences, mixed-effects analysis (group × time) of changes to baseline did not reveal significant differences in the reduction of pain intensity between groups (F2,42=2.5, P=.094). MIVF was not significantly different between groups (F2,43=1.9, P=.159). PTT (F2,43=0.2, P=.854) and daily life impairment (F2,42=1.4, P=.248) were not significantly decreased over time, and there were no differences between groups in the post hoc analysis. CONCLUSIONS DOMS is a common symptom in people participating in exercise, sports, or recreational physical activities. A single treatment with focused extracorporeal shock wave therapy causes clinically relevant effects in the relief of pain, increase in force, and improvement of pain-associated impairments of daily living. Still, results need to be cautiously interpreted because of the pilot character of this study. Focused extracorporeal shock wave therapy might present an option in the midterm recovery from DOMS (72h) and be an approach to enhance the return to play in athletes.