Objective: To determine whether neurocognitive performance and clinical outcomes can be enhanced by a mindfulness intervention in older adults with stress disorders and cognitive complaints. To explore decreased hypothalamic-pituitary-adrenal (HPA) axis activity as a possible mechanism. Methods: 103 adults aged 65 years or older with an anxiety or depressive disorder (diagnosed according to DSM-IV criteria) and subjective neurocognitive difficulties were recruited in St. Louis, Missouri, or San Diego, California, from September 2012 through August 2013 and randomly assigned in groups of 5-8 to mindfulness-based stress reduction (MBSR) or a health education control condition matched for time, attention, and credibility. The primary outcomes were memory (assessed by immediate and delayed paragraph and list recall) and cognitive control (Delis-Kaplan Executive Function System Verbal Fluency Test and Color Word Interference Test). Other outcomes included clinical symptoms (worry, depression, anxiety, and global improvement). HPA axis activity was assessed using peak salivary cortisol. Outcomes were measured immediately postintervention and (for clinical outcomes only) at 3- and 6-month follow up. Results: On the basis of intent-to-treat principles using data from all 103 participants, the mindfulness group experienced greater improvement on a memory composite score (P =.046). Groups did not differ on change in cognitive control. Participants receiving MBSR also improved more on measures of worry (P =.042) and depression (P =.049) at posttreatment and on worry (P =.02), depression (P =.002), and anxiety (P =.002) at follow-up and were more likely to be rated as much or very much improved as rated by the Clinical Global Impressions-Improvement scale (47% vs 27%, χ2 = 4.5, P =.03). Cortisol level decreased to a greater extent in the mindfulness group, but only among those participants with high baseline cortisol. Conclusions: In this population of older adults with stress disorders and neurocognitive difficulties, a mindfulness intervention improves clinical outcomes such as excessive worry and depression and may include some forms of immediate memory performance. © 2017 Physicians Postgraduate Press, Inc.