Background and Objectives: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic renal disease with a complex physiopathology. More and more studies sustain that inflammation plays a crucial role in ADPKD pathogenesis and progression. We evaluated IL-12 involvement in ADPKD pathophysiology by assessing the serum levels of its monomers and heterodimers. Materials and Methods: A prospective case-control study was developed and included 66 ADPKD subjects and a control group of 40 healthy subjects. The diagnosis of ADPKD was based on familial history clinical and imagistic exams. The study included subjects with eGFR > 60 mL/min/1.73 mp, with no history of hematuria or other renal disorders, with stable blood pressure in the last 6 months. We tested serum levels of monomers IL-12 p40 and IL-12 p35 and heterodimers IL-12 p70, IL-23, IL 35, assessed by ELISA method. Results: IL-12 family programming was abnormal in ADPKD patients. IL-12p70, IL-12p40, and IL-23 secretion increased, while IL-12p35 and IL-35 secretion decreased compared to control. IL-12p70, IL-12p40, and IL-23 had a progressive increase correlated with immune response amplification, a decrease of eGFR, an increase in TKV, and in albuminuria. On the other hand, IL-35 and IL-12p35 were correlated negatively with CRP and albuminuria and positively with eGFR in advanced ADPKD. Conclusions: The present study investigated IL-12 cytokine family members’ involvement in ADPKD pathogenesis, enriching our understanding of inflammation in the most common renal genetic disorder.