Background: To investigate the safety and feasibility of image guided immuno-cryotherapy in patients with immune checkpoint inhibitor failure. Methods: Consecutive patients with primary or acquired failure to immune checkpoint inhibitor therapy were studied following treatment with concomitant image-guided cryotherapy and immune checkpoint inhibition. In addition to demographic features, type of malignancy, size of targeted metastatic lesion, number of cycles of cryotherapy, systemic immunotherapy, and adverse events in a 90 day post procedural window were extracted. The primary end point was safety and adverse events stratified by the common terminology for adverse events (CTCAE) criteria. As a secondary endpoint, efficacy of the cryotherapy was assessed by iRECIST. Results: Ten patients underwent combined image-guided cryotherapy and checkpoint immunotherapy between 2015 and 2017. Five patients received CTLA 4 blockade with cryotherapy, and 8 patients received PD1 axis blockade and cryotherapy. Six patients had metastatic non-small cell lung cancer and 4 had metastatic melanoma. Immunoprofiling demonstrated one patient each with a mutation in NRAS (G12C), NRAS (Q61R), KRAS (G12C), and ALK; and 2 with aBRAF V600E mutation. Cryotherapy was performed in immunotherapy failure sites, including liver (5) and adrenal glands (3), lymph node and muscle. The median size of targeted lesions was 4.5 cm (standard deviation 3.7cm). There were no grade 3 or higher adverse event, though 6 patients had grade 1 and 2 adverse effects in the periprocedural period which included fatigue, local pain, and poor appetite, isolated cases of diarrhea, colitis, pneumothorax, and procedural site hematoma. Regarding therapeutic response: 5 patients demonstrated partial response, 1 stable response, and 1 progression of disease. Two patients died in the followup period from non-treatment induced causes and 1 is awaiting follow-up. Disease control rate was 85.7%. Conclusions: Immuno-cryotherapy with immune checkpoint therapy in patients with immune checkpoint inhibitor resistance is safe and feasible in metastatic NSCLC and melanoma. There were no grade 3 or above adverse events.