Background: Existing studies suggested that concomitant use of calcium channel blockers (CCBs) may interfere with the antiplatelet effect of clopidogrel. The objective of this study was to examine the effect of concomitant use of CCBs and clopidogrel on risks of acute coronary syndrome (ACS) re-hospitalization in patients receiving percutaneous coronary intervention. Methods: Using the Taiwan National Health Insurance Research Database, we identified 51 925 patients who were admitted for newly diagnosed ACS, received percutaneous coronary intervention, and used clopidogrel within 1 year after discharge. We further stratified them into three groups based on their uses of guideline-recommended secondary prevention medications for ACS (fully, partially, and non-compliant groups) to assess the potential modification effect of guideline compliance. For each group, we conducted a 1:1 propensity score matching to minimize selection bias. Cox proportional hazard models were used to investigate the effect of concomitant use of CCBs (overall, subclasses, and individual CCBs) and clopidogrel on risks of ACS re-hospitalization. Results: Concomitant use of CCBs in patients discharged with clopidogrel was significantly associated with a lower risk of ACS re-hospitalization in the fully compliant group (HRfully compliant = 0.82 [95% confidence interval 0.75–0.89], p < 0.001) but was associated with increased risk of ACS re-hospitalization in the non-compliant group (HRnon-compliant = 1.22 [1.03–1.45], p = 0.0252). Conclusions: Different guideline compliance of secondary prevention medications could modify the potential drug–drug interaction between clopidogrel and CCBs. Concomitant use of CCBs and clopidogrel was significantly associated with increased risk of ACS re-hospitalization in ACS patients not compliant to guideline-recommended secondary prevention drugs.