UNLABELLED: Mindfulness-based interventions (MBIs) are often promoted in the Western world as being "secular" in nature, despite the religious/spiritual (R/S) roots of mindfulness itself. Relevant individual characteristics such as R/S, however, have yet to be examined thoroughly in relation to treatment response. Using pre-post experimental designs, we examined the interaction of participant religiosity and different religious framings (Buddhist, secular, spiritual) of a brief MBI as determinants of affective responses to the MBI using regression in two online samples (Study 1: =677; Study 2: 157). Aspects of religiosity (existential quest, scriptural literalism) had differential effects on affective responses to MBIs dependent on the framing of the condition. Participants' R/S, as well as the R/S attributes of an MBI, may impact affective responses to MBIs. Further research is needed to ascertain how, and to what extent, MBIs might be optimized in order to maximize benefits for participants with diverse religious and existential commitments. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42761-022-00139-0.