Ability to self-regulate varies and self-regulatory strength is a limited source that can be depleted or fatigued. Research on the impact of individual differences on self-regulatory capacity is still scarce, and this study aimed to examine whether personality factors such as dispositional optimism, conscientiousness, and self-consciousness can impact or buffer self-regulatory fatigue. Participants were patients diagnosed with chronic multi-symptom illnesses ( = 50), or pain free matched controls ( = 50), randomly assigned to either a high or low self-regulation task, followed by a persistence task. Higher optimism predicted longer persistence ( = .04), and there was a trend towards the same effect for conscientiousness ( = .08). The optimism by self-regulation interaction was significant ( = .01), but rather than persisting despite self-regulatory effort, optimists persisted longer only when not experiencing self-regulatory fatigue. The effects of optimism were stronger for controls than patients. There was also a trend towards a similar conscientiousness by self-regulation interaction ( = .06). These results suggest that the well-established positive impact of optimism and conscientiousness on engagement and persistence may be diminished or reversed in the presence of self-regulatory effort or fatigue, adding an important new chapter to the self-regulation, personality, and pain literature.