Objective To evaluate the effect of hyaluronidase in lumbar interlaminar epidural injection (LIEI) for low back pain and sciatica. Method Sixty-one patients suffering from severe low back pain and sciatica were randomly allocated into three groups. Group T (n=18, mean duration of illness: 2.12±1.16 months) received lumbar interlaminar epidural injection (LIEI) with 2 ml triamcinolone (40 mg/ml) and 5 ml bupivacaine (0.25%). Group H (n=16, mean duration of illness: 2.05±1.12 months) received LIEI with 1,500 IU hyaluronidase and 5 ml bupivacaine (0.25%). Group TH (n=27, mean duration of illness: 2.16±1.65 months) received LIEI with 1,500 IU hyaluronidase, 2 ml triamcinolone (40 mg/ml), and 5 ml bupivacaine (0.25%). The effects were evaluated using the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) at preinjection and 2 weeks, 4 weeks, and 8 weeks after LIEI. Results Pain improved in all groups after 2 weeks (p<0.05). After 8 weeks, there was no significant difference in VAS improvement among the 3 groups. However, pain improved in 70.4% of Group TH compared with preinjection, in contrast to 44.4% of Group T and 31.3% of Group H. The ODI improved significantly only in Group TH after 8 weeks (p<0.05). Conclusion LIEI with triamcinolone and hyaluronidase is more effective for reducing pain after 8 weeks than injection with triamcinolone or hyaluronidase alone.