BACKGROUND: Plyometric exercise is used during rehabilitation after anterior cruciate ligament (ACL) reconstruction to facilitate the return to sports participation. However, clinical outcomes have not been examined, and high loads on the lower extremity could be detrimental to knee articular cartilage. PURPOSE: To compare the immediate effect of low- and high-intensity plyometric exercise during rehabilitation after ACL reconstruction on knee function, articular cartilage metabolism, and other clinically relevant measures. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Twenty-four patients who underwent unilateral ACL reconstruction (mean, 14.3 weeks after surgery; range, 12.1-17.7 weeks) were assigned to 8 weeks (16 visits) of low- or high-intensity plyometric exercise consisting of running, jumping, and agility activities. Groups were distinguished by the expected magnitude of vertical ground-reaction forces. Testing was conducted before and after the intervention. Primary outcomes were self-reported knee function (International Knee Documentation Committee [IKDC] subjective knee form) and a biomarker of articular cartilage degradation (urine concentrations of crosslinked C-telopeptide fragments of type II collagen [uCTX-II]). Secondary outcomes included additional biomarkers of articular cartilage metabolism (urinary concentrations of the neoepitope of type II collagen cleavage at the C-terminal three-quarter-length fragment [uC2C], serum concentrations of the C-terminal propeptide of newly formed type II collagen [sCPII]) and inflammation (tumor necrosis factor-alpha), functional performance (maximal vertical jump and single-legged hop), knee impairments (anterior knee laxity, average knee pain intensity, normalized quadriceps strength, quadriceps symmetry index), and psychosocial status (kinesiophobia, knee activity self-efficacy, pain catastrophizing). The change in each measure was compared between groups. Values before and after the intervention were compared with the groups combined. RESULTS: The groups did not significantly differ in the change of any primary or secondary outcome measure. Of interest, sCPII concentrations tended to change in opposite directions (mean +/- SD: low-intensity group, 28.7 +/- 185.5 ng/mL; high-intensity group, -200.6 +/- 255.0 ng/mL; P = .097; Cohen d = 1.03). Across groups, significant changes after the intervention were increased the IKDC score, vertical jump height, normalized quadriceps strength, quadriceps symmetry index, and knee activity self-efficacy and decreased average knee pain intensity. CONCLUSION: No significant differences were detected between the low- and high-intensity plyometric exercise groups. Across both groups, plyometric exercise induced positive changes in knee function, knee impairments, and psychosocial status that would support the return to sports participation after ACL reconstruction. The effect of plyometric exercise intensity on articular cartilage requires further evaluation. REGISTRATION NUMBER: Clinicaltrials.gov NCT01851655.