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Background: Meditation retreats are characterized by intensive or concentrated periods of meditation practice, commonly undertaken in a residential setting. Although research indicates that meditation training can positively influence physical and mental health outcomes, the biological consequences of meditation retreat interventions are relatively understudied. In this study, we examined the influence of a month-long, silent meditation retreat on the expression of genes involved in epigenetic modulation and immune processes. Method: We assessed gene expression changes in experienced meditators attending a month-long Insight meditation retreat (n = 28), as compared to a community control group (n = 34) of experienced practitioners living their everyday lives. Blood samples were collected on day two of the retreat (Time 1) and again 3 weeks later (Time 2). Control participants were also assessed across a 3-week interval, during which they maintained their regular daily routines. Results: As compared to controls, retreat participants showed differential changes in the expression of several genes involved in chromatin modulation and inflammation. The most substantive finding was downregulation of the TNF pathway in retreat participants, which was not observed in controls. Conclusions: These findings indicate that meditation retreat participation may influence some of the inflammatory mechanisms involved in the development of chronic diseases, and that this style of psychosocial intervention may have therapeutic potential, particularly in experienced practitioners.