Introduction: Cryoballoon ablation (CBA) has become a standard treatment for paroxysmal atrial fibrillation (PaAF) but limited data is available for outcomes in patients with persistent atrial fibrillation (PeAF). Methods: We analyzed the first 944 patients included in the Spanish Prospective Multi-center Observation Post-market Registry to compare characteristics and outcomes of patients undergoing CBA for PeAF versus PaAF. Results: A total of 944 patients (57.8 ± 10.4 years; 70.1% male) with AF (27.9% persistent) were prospectively included from 25 centers. PeAF patients were more likely to have structural heart disease (67.7 vs. 11.4%; p < 0.001) and left atrium dilation (72.6 vs. 43.3%; p < 0.001). CBA of PeAF was less likely to be performed under general anesthesia (10.7 vs. 22.2%; p < 0.001), with an arterial line (32.2 vs. 44.6%; p < 0.001) and assisted transeptal puncture (11.9 vs. 17.9%; p = 0.025). During an application, PeAF patients had a longer time to −30 °C (35.91 ± 14.20 vs. 34.93 ± 12.87 s; p = 0.021) and a colder balloon nadir temperature during vein isolation (−35.04 ± 9.58 vs. −33.61 ± 10.32 °C; p = 0.004), but received fewer bonus freeze applications (30.7 vs. 41.1%; p < 0.001). There were no differences in acute pulmonary vein isolation and procedure-related complications. Overall, 76.7% of patients were free from AF recurrences at 15-month follow-up (78.9% in PaAF vs. 70.9% in PeAF; p = 0.09). Conclusions: Patients with PeAF have a more diseased substrate, and CBA procedures performed in such patients were more simplified, although longer/colder freeze applications were often applied. The acute efficacy/safety profile of CBA was similar between PaAF and PeAF patients, but long-term results were better in PaAF patients.