Peyronie's disease (PD) is a chronic inflammatory disease affecting the penile albuginea. Oxidative stress (OS) is important for the development of the disease; therefore, it seemed interesting to us to directly measure OS at both the site of the disease and in peripheral blood. For a precise OS study, it is necessary to evaluate not only the single results of the total oxidant status (TOS) and total antioxidant status (TAS) but also their ratio: OS index (OSI) (arbitrary unit) = TOS/TAS × 100. This study included 49 PD patients examined and diagnosed in our Peyronie's care center and a control group of 50 cases. We collected blood samples from both the penis and a vein in the upper extremity; we used d-ROMs and PAT-test (FRAS kit) for OS measurement. Pearson's study found a statistical correlation between penile OSI values and PD plaque volumes: -value = 0.002. No correlation was found between systemic OSI values and PD plaque volumes: -value = 0.27. Penile OSI values were significantly reduced after the elimination of the PD plaque ( < 0.00001). The mean value of the penile OSI indices in the PD patients after plaque elimination corresponded to 0.090 ± 0.016 ( = 0.004). The comparison between the penile OSI values of the PD patients (with plaque elimination) and the control group revealed no statistically significant differences ( = 0.130). The absence of a correlation between Peyronie's plaque volume and systemic OSI values indicates that it is preferable to carry out the OS study by taking a sample directly from the site of the disease. By carrying out a penile OSI study, it would be possible to obtain a precise plaque-volume-dependent oxidative marker. Even if the study did not demonstrate any correlation between OSI indices and anxious-depressive state, we detected a high prevalence of anxiety (81.6%) and depression (59.1%) in PD patients.