Background/Objectives: Chronic persistent postoperative pain after cardiac surgery, first described as Post CABG Pain Syndrome (PCPS), has been a well-recognized problem since 1989. This study investigated the effect of a single preoperatively administrated pregabalin dose on chronic persistent postoperative pain, in terms of pain intensity, rescue analgesia, and sleep disturbances, after elective cardiac surgery. Methods: This is a secondary analysis of a prospective double-blind single center study that took place in a tertiary/referral center (NCT01701921). Consecutive adult patients who underwent elective cardiac surgery with median sternotomy and extracorporeal circulation under general anesthesia were included. Patients were randomly assigned into three groups {placebo (group 1), oral pregabalin 75 mg (group 2), oral pregabalin 150 mg (group 3)}. Placebo or either dose of pregabalin were administered 1 h preoperatively. Postoperatively at 12 and 24 months, the presence of persistent chronic pain (Numeric Rating Scale, NRS), the need of daily intake of analgesics, and any potential sleep disturbances were assessed. Results: In total, 93 out of 108 patients completed this secondary analysis (86,1%). Patients from all three groups reported persistent postoperative pain at 12 and 24 months, respectively. The mean NRS scores at 12 months were 1.71 (0.588) group 1, 1.23 (0.560) group 2, and 1.19 (0.402) group 3. At 24 months, the mean NRS scores were 1.19 (0.543) Group 1, 0.84 (0.454) Group 2, and 0.84 (0.374) Group 3. No statistically important difference was detected between the two different pregabalin groups. Regarding the use of analgesics, Pearson Chi-Square showed p-values p = 0.027 in 12 months and p = 0.01 in 24 months and lower scores were detected in the high pregabalin dose group. As far as the sleep disturbances are concerned, there was no significant difference between groups. The number of patients who reported persistent postoperative pain at 12 and 24 months was significantly lower in the pregabalin groups (75 mg and 150 mg) than in the placebo group. Regarding the NRS score, Kruskal–Wallis showed a value of p = 0.001 and p = 0.005 in 12 and 24 months respectively. Regarding the use of analgesics, Pearson Chi-Square showed p-values p = 0.027 in 12 months and p = 0.01 in 24 months. Referring to sleep disturbances, there was no significant difference between groups. Conclusions: Based on the results of this study, it seems that oral administration of a single preoperative dose of pregabalin may exhibit a significant preventive effect on chronic persistent postoperative pain after elective cardiac surgery.