Previous animal studies have discovered dysregulation of the local inflammatory state as a novel mechanism to explain structural changes in paraspinal muscles in association with disc degeneration. This study aimed to determine whether the expression of inflammatory genes in the multifidus muscle (MM) differs between individuals with disc degeneration and non-degeneration, which may cause changes in the cross-sectional area (CSA) of paraspinal muscles and clinical outcomes.Muscles were procured from 60 individuals undergoing percutaneous endoscopic lumbar discectomy for lumbar disc herniation (LDH). Total and functional CSAs and fatty degeneration of paraspinal muscles on ipsilateral and unilateral sides were measured. Gene expression was quantified using qPCR assays. Paired t-test and Pearson's correlation analysis were used to compare the mean difference and associations, respectively.There were significant differences in total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM between ipsilateral and unilateral sides. Participants in the disc degeneration group displayed higher fat infiltration in MM. The expression of TNF was moderately correlated with total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM. The expression of IL-1β was strongly correlated with the total and functional CSA of MM. The expression of TGF-β1 was moderately correlated with the functional CSA of MM. The expression of TNF, IL-1β, and TGF-β1 was moderate to strongly correlated with clinical outcomes.The results show that there were differences in the characteristics of paraspinal muscles between the ipsilateral and unilateral sides, which were affected by disc degeneration and the degree of fat infiltration. High-fat filtration and reduction of CSA of MM are associated with inflammatory dysfunction. There was evidence of a dysregulated inflammatory profile in MM in individuals with poor clinical outcomes.© 2023. The Author(s).