Abstract Open label placebos (OLPs) appear generally efficacious among clinical samples, but the empirical evidence regarding their use in non‐clinical and sub‐clinical samples, as well as when administered independent of a convincing rationale, is mixed. Healthy participants ( N = 102) were randomised to either a 6‐day course of OLP pills with information provision (OLP‐plus: N = 35), without information provision (OLP‐only: N = 35), or no‐treatment control group ( N = 32). OLP pills were described as enhancing physical (symptoms and sleep) and psychological (positive and negative emotional) well‐being. Well‐being was assessed at baseline and on Day 6. Expectancies and adherence were measured. OLP administration interacted with baseline well‐being. The OLP‐plus group demonstrated increased well‐being on all outcomes other than positive emotions, but only when they reported decreased baseline well‐being. OLP‐only and control groups did not differ. The OLP‐plus group demonstrated elevated expectancies, that mediated the OLP effect on physical symptoms relative to control, but only when well‐being was lower than average at baseline (i.e. moderated‐mediation). Results demonstrate the importance of information provided with OLPs. The moderating effect of baseline outcomes may reconcile inconsistent results regarding clinical and non‐clinical samples. Accounting for baseline symptoms in non‐clinical and sub‐clinical samples is likely to enhance our understanding of when OLPs are effective.