Vulnerable women living in poverty in Uganda, who are primarily single, illiterate mothers, face high levels of physical and psychological stress. Our study assessed the impact of the Transcendental Meditation® (TM®) technique on self-efficacy, perceived stress, and mental and physical quality of life of these women. This single-blind controlled study involved 81 women who were assigned to either practice of the Transcendental Meditation program (n = 42) or wait-list (delayed start) control group (n = 39). Participants learned the Transcendental Meditation program over five sessions, then practiced at home for 20 minutes twice a day, and attended twice monthly group meetings over a 3-month period. The primary outcome measure was self-efficacy using the General Self-Efficacy Scale (GSES). Perceived stress using Cohen's Perceived Stress Scale, and physical and mental quality of life using subscales of the Medical Outcomes Survey (MOS, HIV version) were secondary outcome measures. Significant improvements were shown in self-efficacy (p < .001), perceived stress (p < .010), and mental and physical well-being (p < .010). Compliance with TM home practice was >88%. This is the first controlled study to demonstrate the effect of TM in the daily lives of mothers living in impoverished conditions. Further questionnaires were administered to participants at 8 months and at 36 months with questions about changes they may have experienced in their daily life since starting TM. "Yes," "No" self-reported answers suggested that the women experienced improved health, improved relationships with others, and increased employment rates. These findings taken as a whole have important implications for developing self-efficacy, improving mental and physical quality of life, and reducing stress in the lives of these vulnerable women.