Treatment effect modifiers identify patient characteristics associated with treatment responses. The purpose of this secondary analysis was to identify potential treatment effect modifiers for disability from the TARGET trial that compared usual care (control) with usual care + psychologically informed physical therapy (PIPT). The sample consisted of a STarT Back tool identified high-risk patients with acute low back pain that completed Oswestry Disability Index (ODI) data at index visit and 6 months later (n = 1250). Candidate treatment effect modifiers were identified a priori and informed by the literature. Linear mixed models tested for treatment effect modification through tests of statistical interaction. All statistical interactions ( P ≤ 0.20) were stratified by modifier to inspect for specific effects ( P ≤ 0.05). Smoking was identified as a potential effect modifier (treatment * smoking interaction, P = 0.08). In participants who were smokers, the effect of PIPT was (ODI = 5.5; 95% CI: 0.6-10.4; P = 0.03) compared with usual care. In participants who were nonsmokers, the effect of PIPT was (ODI = 1.5; 95% CI: -1.4 to 4.4; P = 0.31) compared with usual care. Pain medication was also identified as a potential effect modifier (treatment × pain medication interaction, P = 0.10). In participants prescribed ≥3 pain medications, the effect of PIPT was (ODI = 7.1; 95% CI: -0.1 to 14.2; P = 0.05) compared with usual care. The PIPT effect for participants prescribed no pain medication was (ODI = 3.5; 95% CI: -0.4 to 7.4; P = 0.08) and for participants prescribed 1 to 2 pain medications was (ODI = 0.6; 95% CI: -2.5 to 3.7; P = 0.70) when compared with usual care. These findings may be used for generating hypotheses and planning future clinical trials investigating the effectiveness of tailored application of PIPT.