Background: The adoption of immunotherapy has led to a paradigm shift in the treatment of many advanced stage malignancies. Patients with durable long term survival under cancer immunotherapy have begun to emerge. Circulating memory immune T and B-cells play a key role in the anamnestic response to future similar antigen exposure and may contribute to durable cancer immunotherapy response and benefits in patients with irAE. We hypothesized that there is increased median overall survival (mOS) in patients who had irAE under CPI therapy. Methods: We conducted a retrospective analysis with an IRB-approved study protocol of adults treated between 2011-2019 at the West Virginia University Cancer Institute, with a histopathologic diagnosis of melanoma or lung cancer, who had received CPI therapy. We collected data on demographics, histology, stage at diagnosis, immunotherapy type used, irAE and its grade, and days from immunotherapy initiation to death. Patients were stratified by irAE status and CPI rechallenge status following irAE. Results: Demographics were similar between the irAE and non-irAE groups within both cancer types. A total of 229 lung and 114 melanoma cancer patients had received CPI. Overall, there were 105/343 (30.6%) cases of irAE found of any grades: 27.5% of lung and 37.7% of melanoma patients developed irAE. The mOS for the non-irAE cohort group was 299 days, which was significantly worse than the irAE cohort (mOS not met, Log-rank, p < 0.0001). Within the irAE cohort, there was no significant survival difference between the non-rechallenged and rechallenged groups (Log-rank p = 0.6150). Conclusions: Our findings identified significantly improved survival outcomes among lung cancer/melanoma patients treated with CPI who developed irAE, including those who were rechallenged after irAE, compared to those who had no irAE. Patients who were CPI-rechallenged after irAE had comparable survival outcomes compared to those without rechallenge. Further multi-center validation studies and prospective studies are warranted to further confirm these findings and help guide clinical management in patients who experience CPI irAE.