Shoulder pain is a highly prevalent musculoskeletal condition that frequently leads to suboptimal clinical outcomes. This study tested the extent to which circulating inflammatory biomarkers are associated with reports of shoulder pain and upper-extremity disability for a high-risk genetic by psychological subgroup (catechol-O-methyltransferase [COMT] variation by pain catastrophizing [PCS]). Pain-free adults meeting high-risk COMT × PCS subgroup criteria completed an exercise-induced muscle injury protocol. Thirteen biomarkers were collected and analyzed from plasma 48 hours after muscle injury. Shoulder pain intensity and disability (Quick-DASH) were reported at 48 and 96 hours to calculate change scores. Using an extreme sampling technique, 88 participants were included in this analysis. After controlling for age, sex, and BMI, there were moderate positive associations between higher c-reactive protein (CRP; βˆ = .62; 95% confidence interval [CI] = -.03, 1.26), interleukin-6 (IL-6; βˆ = 3.13; CI = -.11, 6.38), and interleukin-10 (IL-10; βˆ = 2.51; CI = -.30, 5.32); and greater pain reduction from 48 to 96 hours post exercise muscle injury. Using an exploratory multivariable model to predict pain changes from 48 to 96 hours, we found participants with higher IL-10 were less likely to experience a high increase in pain (βˆ = -10.77; CI = -21.25, -2.69). Study findings suggest CRP, IL-6, and IL-10 are related to shoulder pain change for a preclinical high-risk COMT × PCS subgroup. Future studies will translate to clinical shoulder pain and decipher the complex and seemingly pleiotropic interplay between inflammatory biomarkers and shoulder pain change. PERSPECTIVE: In a preclinical high-risk COMT × PCS subgroup, 3 circulating inflammatory biomarkers (CRP, IL-6, and IL-10) were moderately associated with pain improvement following exercise-induced muscle injury.