Introduction Pegloticase, a potent uricolytic biologic enzyme, has been shown to be an effective therapeutic option in patients with uncontrolled gout. However, there are limited data on clinical response after a gap in therapy and retreatment with pegloticase. Case Series This report describes four patients with chronic gout who were successfully managed with pegloticase and were retreated following a gap in therapy. Patient charts from a practice-based rheumatology clinic were retrospectively analyzed; four male patients, aged 70–75 years, with chronic gout and a more than 4-week gap in pegloticase therapy were reviewed. Before pegloticase treatment, patients had received allopurinol or febuxostat, but they continued exhibiting symptoms, including visible tophi and serum uric acid (SUA) levels of 5.2–10.2 mg/dL (309–607 μmol/L), despite oral urate-lowering therapy. The first pegloticase treatment (8-mg infusion every 2 weeks) lasted 22–124 weeks. Pegloticase resolved tophi and improved SUA to below 1.5 mg/dL (less than 89 μmol/L); however, patients discontinued pegloticase because of symptom resolution, poor adherence, or personal reasons. Following treatment gaps (12–156 weeks), symptoms and SUA levels increased and patients were retreated with pegloticase (4–147 weeks). In three of four patients, reinitiating pegloticase lowered SUA levels to below 1.0 mg/dL (less than 59 μmol/L) and resolved symptoms. One patient experienced an infusion reaction and discontinued; no infusion reactions, gout flares, or adverse events occurred among the other three patients. Conclusion Retreatment with pegloticase after a gap in therapy appears to be an effective and tolerated option in prior responders. Funding Horizon Pharma.