Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation (PESE) or post-exertional neuroimmune exhaustion (PENE), is a worsening of symptoms that occurs after minimal exertion. It is the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and common in long COVID and fibromyalgia. PEM is often severe enough to be disabling, and is triggered by ordinary activities that healthy people tolerate. Typically, it begins 12–48 hours after the activity that triggers it, and lasts for days, but this is highly variable and may persist much longer. Management of PEM is symptom-based, and patients are recommended to pace their activities to avoid triggering PEM.

One of the first definitions of ME/CFS, the Holmes Criteria published in 1988, does not use the term post-exertional malaise but describes prolonged fatigue after exercise as a symptom. The term was later used in a 1991 review summarizing the symptoms of ME/CFS. Afterwards, the Canadian Consensus Criteria from 2003 and the International Consensus Criteria from 2011 used the term, as well as later definitions.

The 2021 NICE committee stated they consider the term PEM outdated, as it may give the impression of just a "vague discomfort", and argued that the term post-exertional symptom exacerbation better captures the symptom. Nonetheless, they decided to continue using PEM as it is the more familiar term.

Fatigue is often prominent in PEM symptoms, but it is "more than fatigue following a stressor". Other symptoms that may occur during PEM include cognitive impairment, flu-like symptoms, pain, weakness, and trouble sleeping. Though typically cast as a worsening of existing symptoms, patients may experience some symptoms exclusively during PEM. Patients often describe PEM as a "crash", "relapse", or "setback".

Symptoms typically begin 12–48 hours after the triggering activity, but may be immediate, or delayed up to 7 days. PEM lasts "usually a day or longer", but can span hours, days, weeks, or months. PEM involves an exacerbation of symptoms, or the appearance of new symptoms, which are often severe enough to impact a person's functioning.

PEM is triggered by "minimal" physical or mental activities that were previously tolerated, and that healthy people tolerate, like attending a social event, grocery shopping, or even taking a shower. Sensory overload, emotional distress, injury, sleep deprivation, infections, and spending too long standing or sitting up are other potential triggers. The resulting symptoms are disproportionate to the triggering activity and are often debilitating, potentially rendering someone housebound or bedbound until they recover.

The level of activity that triggers PEM, as well as the symptoms, vary from person to person, and within individuals over time. Due to this variability, affected people may be unable to predict what will trigger it. This variable, relapsing-remitting pattern can cause one's abilities to fluctuate from one day to the next.

PEM is a hallmark symptom of ME/CFS and is common in long COVID.