Background: The DE-imFAR study aims to compare the effectiveness of several de-implementation strategies targeting clinicians' decision-making processes to reduce potentially inappropriate prescribing (PIP) of statins for cardiovascular disease (CVD) primary prevention. Methods: A partially randomized, cluster implementation trial with an active comparator group, involving family physicians (FPs) with non-zero incidence rates of PIP of statins in 2021, was conducted in 13 integrated healthcare organizations (IHOs) in the Basque Health Service. All eligible FPs (n = 621) were exposed to (1) a non-reflective decision assistance (DA) strategy based on reminders. FPs from two IHOs were randomized to additionally receive one of two increasingly intensive reflective strategies: (2) a knowledge dissemination decision information (DI) strategy (n = 59), or (3) a DI strategy plus audit and feedback (A&F) self-reflective decision (SRD) strategy (n = 59). The main outcome was the change from baseline to 12 months after deployment in the likelihood of receiving new PIP of statins and advice on lifestyle modifications, estimated with generalized mixed effects models, in 45- to 74-year-old low cardiovascular risk patients with elevated cholesterol levels but no diagnosed CVD. Results: After FPs' exposure to the corresponding strategies, rates of statin PIP decreased significantly in all groups (p < 0.001). Concerning study's main observational comparisons between strategies, though the reduction obtained by the DI and SRD strategies were 33% (adjusted OR: 0.77; 95% CI: 0.58-1.01) and 6% (aOR: 0.94; 95% CI: 0.73-1.23) higher compared to the change from the DA, estimated differences did not reach statistical significance (p = 0.07). When comparing the two reflective strategies together (DI + SRD) with the non-reflective (DA), a significant difference (p = 0.038) was observed, being the odds of receiving PIP of statins 19% lower (aOR: 0.81; 95% CI: 0.66-0.99). In the experimental comparison between reflective strategies (SRD vs. DI), providing A&F to FPs showed no additional effect (p = 0.30). Conclusions: De-implementation strategies that targeted clinical decision-making were effective in reducing PIP of statins for CVD primary prevention. Strategies that targeted reflective thinking and increased awareness of low-value prescribing showed a trend toward greater effectiveness.