Background/Objectives: We conducted the first pharmacogenetic investigation of atopic dermatitis in a cohort of 43 Greek patients, focusing on key variants within the IL6/JAK/STAT signaling axis, a pathway central to inflammation and therapeutic targeting. Methods: Patients receiving dupilumab, JAK inhibitors, or topical corticosteroids were prospectively evaluated, with treatment response assessed by changes in the Eczema Area and Severity Index over four months. Targeted genotyping of IL6R rs2228145 A>C, JAK1 rs2780815 T>G, and TRAF3 rs12147254 G>A were performed using PCR-RFLP. Results: Across the full cohort, no robust pharmacogenetic effects were detected, while baseline disease severity was the strongest predictor of absolute clinical improvement. However, stratified analyses revealed a significant association between the IL6R rs2228145 minor allele and reduced upadacitinib response (p-value = 0.026). Consistently, the same variant demonstrated a nominal association with reduced likelihood of achieving ≥75% improvement (p = 0.065). Conclusions: Although limited by sample size, these findings suggest potential treatment-specific pharmacogenetic effects within the IL6 pathway, supporting further investigation in larger cohorts to inform personalized therapeutic strategies in eczema.