Background: The minimum clinically important difference (MCID) is used to interpret the relevance of treatment effects, e.g., when developing clinical guidelines, evaluating trial results or planning sample sizes. There is currently no agreement on an appropriate MCID in chronic pain and little is known about which contextual factors cause variation. Methods: This is a systematic review. We searched PubMed, EMBASE, and Cochrane Library. Eligible studies determined MCID for chronic pain based on a one-dimensional pain scale, a patient-reported transition scale of perceived improvement, and either a mean change analysis (mean difference in pain among minimally improved patients) or a threshold analysis (pain reduction associated with best sensitivity and specificity for identifying minimally improved patients). Main results were descriptively summarized due to considerable heterogeneity, which were quantified using meta-analyses and explored using subgroup analyses and metaregression. Results: We included 66 studies (31.254 patients). Median absolute MCID was 23 mm on a 0–100 mm scale (interquartile range [IQR] 12–39) and median relative MCID was 34% (IQR 22–45) among studies using the mean change approach. In both cases, heterogeneity was very high: absolute MCID I2 = 99% and relative MCID I2 = 96%. High variation was also seen among studies using the threshold approach: median absolute MCID was 20 mm (IQR 15–30) and relative MCID was 32% (IQR 15–41). Absolute MCID was strongly associated with baseline pain, explaining approximately two-thirds of the variation, and to a lesser degree with the operational definition of minimum pain relief and clinical condition. A total of 15 clinical and methodological factors were assessed as possible causes for variation in MCID. Conclusions: MCID for chronic pain relief vary considerably. Baseline pain is strongly associated with absolute, but not relative, measures. To a much lesser degree, MCID is also influenced by the operational definition of relevant pain relief and possibly by clinical condition. Explicit and conscientious reflections on the choice of an MCID are required when classifying effect sizes as clinically important or trivial.