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Uncertainty about symptom duration, cause, prognosis and treatment is common in patients who seek medical care, yet individual ability to manage this uncertainty varies. Intolerance of uncertainty is considered an important factor in the etiology and persistence of negative emotions- in particular, depression and anxiety. We explored the contribution of intolerance of uncertainty to anxiety due to pain and physical function in patients seeking care at an orthopedic medical practice. Participants (N = 105, mean age of 51 ± 17, 63% male) were administered PROMIS Physical Function v1.2 Upper Extremity CAT, Numerical Rating Scale (NRS), Pain Anxiety Symptoms Scale-short form (PASS-20), and the Intolerance of Uncertainty Scale-short version (IUS-12). Results showed that the mediating role of pain anxiety is contingent upon the level of intolerance of uncertainty. Specifically, a minimum level of intolerance of uncertainty is required for the development of pain anxiety and its effect on function, and as intolerance of uncertainty rises from low to medium to high levels, the effect of pain on function goes from being independent of the anxiety to being more and more carried by and through anxiety about pain. These findings support the contention that intolerance of uncertainty plays a crucial role in the relationship between pain, pain anxiety, and physical function. Intolerance of uncertainty appears to be a trans-diagnostic target for coping skills training., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)