OBJECTIVE: To examine the effects of a comprehensive residential mind-body program on well-being. DESIGN: The Self-Directed Biological Transformation Initiative was a quasi-randomized trial comparing the effects of participation in a 6-day Ayurvedic system of medicine-based comprehensive residential program with a 6-day residential vacation at the same retreat location. SETTING: Retreat setting. PARTICIPANTS: 69 healthy women (n = 58) and men (n = 11) (mean age ± standard deviation, 53.6 ± 12 years). INTERVENTION: The Ayurvedic intervention addressed physical and emotional well-being through group meditation and yoga, massage, diet, adaptogenic herbs, lectures, and journaling. OUTCOME MEASURES: A battery of standardized questionnaires. RESULTS: Participants in the Ayurvedic program showed significant and sustained increases in ratings of spirituality (p < 0.01) and gratitude (p < 0.05) compared with the vacation group, which showed no change. The Ayurvedic participants also showed increased ratings for self-compassion (p < 0.01) as well as less anxiety at the 1-month follow-up (p < 0.05). CONCLUSIONS: Findings suggest that a short-term intensive program providing holistic instruction and experience in mind-body healing practices can lead to significant and sustained increases in perceived well-being and that relaxation alone is not enough to improve certain aspects of well-being.