Abstract Aims Lumbar radicular pain after disc herniation may be associated release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. Methods First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ on the dorsal horn single cell activity and gene expression close to the nerve roots was studied. Second, in patients with severe lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) important for the IFN-γ expression influenced the pain and disability measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI). Results The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the nerve-roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also observed. Moreover, the data of the patients revealed that carriers of the IFN-γ SNPs; rs2069705 A allele and rs2069718 G allele had an increased disability score i.e. ODI. Conclusions The present data suggest that IFN-γ through activation of tissue-specific macrophages close to the nerve roots may be important for acute inflammatory pain and disability following lumbar disc herniation.