Within this single-center cohort study, we investigated the impact of optimal medical therapy on all-cause mortality, major amputation-free survival and clinically driven target lesion revascularization (CD TLR) in 552 patients with peripheral arterial disease (PAD) undergoing endovascular infrapopliteal revascularization. From the overall cohort, 145 patients were treated for intermittent claudication (IC) and 407 were treated for critical limb ischemia (CLI). Optimal medical therapy (OMT) was defined as the presence of at least one antiplatelet agent, statin and ACE inhibitor or AT-2 antagonist based on guideline recommendations. About half (55.5%) of all patients were prescribed OMT at discharge, with a higher proportion in claudicants (62.1%) versus CLI patients (53.2%). Over three years of follow-up, survival was significantly better in patients with IC (80.6 ± 3.8% vs. 59.9 ± 2.9%; p < 0.001). There was a signal towards better survival in those patients receiving OMT (log-rank p = 0.09). Similarly, amputation-free survival (AFS) was significantly better in patients with IC (p = 0.004) and also in patients receiving OMT (78.8 ± 3.6%) compared to that in those without OMT (71.5 ± 4.2%; p = 0.046). Freedom from CD TLR within three years was significantly better in the IC group (p = 0.002), but there were no statistically significant differences for CD TLR dependent on the presence of OMT (p = 0.79). In conclusion, there is still an important underuse of OMT in patients undergoing infrapopliteal interventions, which is even more pronounced in CLI despite a signal for its benefit regarding all-cause mortality and major amputation-free survival.