Abstract The current pilot study examines the effects of a mindfulness intervention versus relaxation-based active control on psychophysiological reactivity measured by heart rate (HR), high-frequency heart rate variability (HF-HRV), skin conductance level (SCL), and number of skin conductance responses (SCR) in adolescents. A total of 110 students, ages 12 and 15, participated from four schools. The conditions of a 9-week mindfulness intervention or a relaxation-based active control were randomly assigned to schools. At the baseline (preintervention), participants completed a test protocol with three different tasks: an arithmetic task, a minimal stress task, and a social stress-inducing speech task, divided into argue, oppose, and comment subtasks. The test protocol was repeated postintervention at 9 weeks and followed up at 26 weeks. For the speech task (oppose), the number of SCRs increased in the control group during both (9-week and 26-week) follow-ups, but stayed at the same level in the intervention group (i.e., the stress response in the control group increased). Additionally, HR and SCL reactivity were close to significance, demonstrating an increase in the control group and increased stress. There were no significant differences in HR, HF-HRV, and SCL between the intervention and control groups. The results of this pilot study suggest that in a highly stressful social situation, mindfulness, compared to the active control, might have a subtle effect in lowering sympathetically driven physiological stress reactivity. Other measures show either no effects or tentative findings that should be addressed in future studies with larger samples.