A prospective randomized study involving 280 consecutive cases of lumbar disc herniation managed either by an endoscopic discectomy alone or an endoscopic discectomy combined with an intradiscal injection of a low dose (1000 U) of chymopapain. To compare outcome, complications, and reherniations of both techniques. Despite a low complication rate, posterolateral endoscopic nucleotomy has made a lengthy evolution because of an assumed limited indication. Chemonucleolysis, however, proven to be safe and effective, has not continued to be accepted by the majority in the spinal community as microdiscectomy is considered to be more reliable. A total of 280 consecutive patients with a primary herniated, including sequestrated, lumbar disc with predominant leg pain, was randomized. A clinical follow-up was performed at 3 months, and at 1 and 2 years after the index operation with an extensive questionnaire, including the visual analog scale for pain and the MacNab criteria. The cohort integrity at 3 months was 100%, at 1 year 96%, and at 2 years 92%. At the 3-month evaluation, only minor complications were registered. At 1-year postoperatively, group 1 (endoscopy alone) had a recurrence rate of 6.9% compared to group 2 (the combination therapy), with a recurrence rate of 1.6%, which was a statistically significant difference in favor of the combination therapy (P = 0045). At the 2-year follow-up, group 1 reported that 85.4% had an excellent or good result, 6.9% a fair result, and 7.7% were not satisfied. At the 2-year follow-up, group 2 reported that 93.3% had an excellent or good result, 2.5% a fair result, and 4.2% were not satisfied. This outcome was statistically significant in favor of the group including chymopapain. There were no infections or patients with any form of permanent iatrogenic nerve damage, and no patients had a major complication. A high percentage of patient satisfaction could be obtained with a posterior lateral endoscopic discectomy for lumbar disc herniation, and a statistically significant improvement of the results was obtained when an intradiscal injection of 1000 U of chymopapain was added. There was a low recurrence rate with no major complications. The method can be applied in any type of lumbar disc herniation, including the L5-S1 level.