Aims This study aimed to analyze the cost-effectiveness of intradiscal condoliase injection compared to surgical or conservative treatment for patients with lumbar disc herniation (LDH) who are refractory to conservative treatment. Methods We performed the following cost-effectiveness analyses: (I) condoliase followed by open surgery (for non-responders to condoliase) vs. open surgery from the beginning, (II) condoliase followed by endoscopic surgery (for non-responders to condoliase) vs. endoscopic surgery from the beginning, and (III) condoliase + conservative treatment vs. conservative treatment. In the first two comparisons with surgical treatments, we assumed that utilities were equal in both groups and estimated the tangible (treatment, adverse events, postoperative follow-up) and intangible (mental and physical burden, and productivity loss) costs based on the existing literature, the medical expense scoring table, and online questionnaire. In the last comparison without surgical treatment, we estimated the incremental cost-effectiveness. Results The average cost per patient of condoliase followed by open surgery (for non-responders to condoliase) was 701,643 yen, with a reduction of 663,369 in comparison to that of open surgery from the beginning (1,365,012 yen). The average cost per patient of condoliase followed by endoscopic surgery (for non-responders to condoliase) was 643,909 yen, with a reduction of 514,909 in comparison to that of endoscopic surgery from the beginning (1,158,817 yen). ICER was 1.58 million yen/QALY (Delta QALY = 0.119, 95% confidence interval: 0.059-0.180; Delta cost = 188,809 yen at 2 years post-treatment). Conclusions Condoliase as a first line treatment option ahead of surgical treatment for LDH is superior, from a cost perspective, to surgical treatment from the beginning. Condoliase is also a cost-effective alternative to non-surgery conservative treatment.