Introduction There is little evidence to suggest that one educational intervention is superior to another when associated with a rehabilitation program in the management of persistent low back pain. The objective of the present study was to compare pain neuroscience education with spine physiology and ergonomics education as part of a one-week multidisciplinary rehabilitation program. Method We conducted a randomized, controlled trial among patients having experienced persistent low back pain for at least 1 year. The patients participated in a one-week multidisciplinary rehabilitation program with an educational component. The members of the experimental and control groups received pain neuroscience education and spine physiology and ergonomics education, respectively. Outcomes were assessed before the program (day 0), immediately afterwards (day 5), and on day 90 after the start of the program. The primary outcome measure was functional disability on day 90. Results A total of 88 patients were randomized. On day 90, a statistically significant mean [95% confidence interval] decrease in the level of disability was observed in the experimental (PNE) group (−3.4 [-5.0 to −1.8]). The mean [95%CI] difference versus the control group (−1.7 [-4.0 to 0.5]) was not statistically significant (p = 0.12). There were no statistically significant intergroup differences in the secondary outcome measures. Conclusion There appears to be no advantage in replacing a conventional, non-neuroscientific educational program (based on spinal physiology and ergonomics) with a pain neuroscience education program as part of a one-week multidisciplinary rehabilitation program. Further research is needed to identify patients who will respond better to a pain neuroscience education module as part of a personalized care program.