Self-affirmation theory (SAT) and acceptance and commitment therapy (ACT) embody competing approaches to leveraging personal values to motivate behavior change but are rarely compared in the domain of health behavior. This study compares these theory-driven values-based interventions for promoting medication adherence. To compare affective and behavioral responses to competing values-based medication adherence interventions. In this three-armed randomized trial, participants with cancer (n = 95) or diabetes (n = 97) recruited online using Prolific and prescribed daily oral medication for that disease completed a one-session online writing intervention leveraging (1) a domain incongruent (DI) value, where the value was not connected to medication adherence; (2) a domain congruent (DC) value, where the value was connected to adherence; or (3) a control condition, focused on medication adherence procedures. There were no main effects of conditions on reported medication adherence at the 1-month follow-up. During the intervention, positive affect was higher in the values conditions than control (p < .001), and trended higher in DI versus DC (p = .054). Negative affect did not vary between the values and control groups (p = .093) but was lower in DI versus DC (p = .006). Improvements in positive affect over the course of the intervention were associated with increased adherence behavior for individuals who started with low levels of positive affect (p = .003). Disease type did not moderate findings. Consistent with SAT, focusing on DI values led to more positive and less negative affect than connecting values directly to behavior in a threatening domain such as chronic illness. For some participants, increases in positive affect predicted greater adherence.