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Multicentered randomized controlled trial.To determine if previously validated low back pain (LBP) subgroups respond differently to contrasting exercise prescriptions.The role of “patient-specific” exercises in managing LBP is controversial.A total of 312 acute, subacute, and chronic patients, including LBP-only and sciatica, underwent a standardized mechanical assessment classifying them by their pain response, specifically eliciting either a “directional preference” (DP) (i.e., an immediate, lasting improvement in pain from performing either repeated lumbar flexion, extension, or sideglide/rotation tests), or no DP. Only DP subjects were randomized to: 1) directional exercises “matching” their preferred direction (DP), 2) exercises directionally “opposite” their DP, or 3) “nondirectional” exercises. Outcome measures included pain intensity, location, disability, medication use, degree of recovery, depression, and work interference.A DP was elicited in 74% (230) of subjects. One third of both the opposite and non-directionally treated subjects withdrew within 2 weeks because of no improvement or worsening (no matched subject withdrew). Significantly greater improvements occurred in matched subjects compared with both other treatment groups in every outcome (P values <0.001), including a threefold decrease in medication use.Consistent with prior evidence, a standardized mechanical assessment identified a large subgroup of LBP patients with a DP. Regardless of subjects’ direction of preference, the response to contrasting exercise prescriptions was significantly different: exercises matching subjects’ DP significantly and rapidly decreased pain and medication use and improved in all other outcomes. If repeatable, such subgroup validation has important implications for LBP management.