This short paper aims to untangle the effect of loss-framing versus gain and non-gain; explaining when, how and why it influences individuals' intentions to engage in cholesterol screening. We argue that framing-effects are (1) significant only when individuals perceive the issue to be highly relevant and (2) are mediated by perceived negative consequences (resulting from undergoing the test) and response-efficacy. In a 2(issue-relevance: high vs low) × 3(framing: gain vs non-gain vs loss) experiment, 229 participants received a message and answered to a questionnaire measuring personal relevance, perceived negative consequences, response-efficacy, intention. Results validated a mediation model, explaining that loss-framing is more persuasive than non-gain, which is more persuasive than gain-framing, partly because of their effect on individuals' perceptions of response-efficacy.