Purpose: To study the interaction between Modic changes (MC) and inflammation by macrophages in the disc, in relation to clinical symptoms before and after discectomy for lumbar disc herniation. Methods: Disc tissue was embedded in paraffin and stained with haematoxylin and CD68. Subsequently, tissue samples were categorized for degree of inflammation. Type of MC was scored on MRI at baseline. Roland Disability Questionnaire (RDQ) score and visual analogue scale for back pain and leg pain separately were considered at baseline and 1-year follow-up post-surgery. Main and interaction effects of MC and inflammation were tested against clinical outcome questionnaires. In addition, this analysis was repeated in bulging and extruded discs separately. Results: Disc material and MRI’s of 119 patients were retrieved and analysed. Forty-eight patients demonstrated mild inflammation, 45 showed moderate inflammation, and 26 showed considerable inflammation. In total, 49 out of 119 patients demonstrated MC. Grade of disc inflammation did not associate with the presence of MC. At baseline, no main or interaction effects of MC and inflammation were found on the clinical scores. However, during follow-up after discectomy, significant interaction effects were found for RDQ score: Only in patients with MC at baseline, patients remained significantly more disabled (3.2 points p = 0.006) if they showed considerable disc inflammation compared to patients with mild inflammation. The additional analysis showed similar results in extruded discs, but no significant effects in bulging discs. Conclusions: An interaction effect of MC and disc inflammation by macrophages is present. Only in patients with MC, those with considerable inflammation recover less satisfactory during follow-up after surgery. Graphic abstract: These slides can be retrieved under Electronic Supplementary Material.[Figure not available: see fulltext.].