Background: Inflammation plays an important role in the initiation of atrial fibrillation (AF) and the development of fibrosis following pulmonary vein isolation (PVI). We aimed to investigate whether early post-PVI levels of C-reactive protein (CRP), white blood cells, tumour necrosis factor alpha (TNF-α) and transforming growth factor beta 1 (TGF-ß1) are associated with long-term arrhythmia recurrence. Methods: This prospective observational study included 48 patients with paroxysmal AF undergoing PVI. Peripheral venous blood samples were collected on the day of hospitalisation (T0), immediately after the procedure (T1) and after 24 h (T2), seven days (T3) and one month (T4) following the procedure. Blood samples were obtained from the coronary sinus (CS) before and after PVI. CRP levels, leukocyte (LKc) and neutrophile (Neu) counts were determined. TGF-β1 and TNF-α were analysed using the enzyme-linked immunosorbent assay (ELISA). After discharge, follow-up visits were scheduled at seven days and one-, three-, six-, nine- and twelve-months post-ablation, with 24 h Holter monitoring at each visit. Results: Patients were allocated into a recurrent and a non-recurrent group. Baseline characteristics did not differ between the groups, except for the duration of AF, which was found to be a significant arrhythmia recurrence predictor. Patients in the non-recurrent group had statistically significantly higher LKc at all time points, and Neu at T2 and T3. CRP and TGF-β1 concentrations were significantly higher in the non-recurrent group, while TNF-α concentration was significantly higher in the recurrent group at the T2 time point. Significantly higher concentrations of CS TNF-α at T1 and TGF-β1 at T0 and T1 were documented in the non-recurrent group. Conclusions: The study shows that an enhanced inflammatory response early after PVI, characterised by increased CRP, WBC and TGF-β1 levels, may play a protective role against late arrhythmia recurrence.