Background: Clinical responses to PD1 blockade have been linked to IFN-γ associated gene expression in the tumor microenvironment. Stereotactic body radiotherapy (SBRT) can stimulate innate and adaptive immunity to potentially augment immunotherapy. Anti-PD1 treatment outcomes are improved with lower disease burden and multi-site radiation is an emerging paradigm for eradicating metastatic disease. Methods: We conducted a phase I study for patients with metastatic solid tumors who progressed on standard treatment. The primary aim was to evaluate the safety of pembrolizumab Immunotherapy with Multi-Organ Site Ablative stereotactic body Radiation Therapy (iMOSART). Two to four metastases were chosen for each patient and not all sites of disease were targeted with SBRT. Metastases > 65cc were partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. Results: 79 patients were enrolled, three patients did not receive any treatment and three patients only received SBRT. The 73 patients included in the analysis were treated with SBRT and at least 1 cycle of pembrolizumab. 94.5% of patients had two lesions treated with SBRT. Median follow-up for toxicity was 5.5 months (IQR 3.3-8.1). Six patients experienced dose-limiting toxicity (DLT) with no radiation dose reductions. RECIST overall objective response rate was 13.5% in the 68 patients with imaging follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target lesions for the 52 patients with paired data (p = 0·0005) with a mean percent tumor burden change -21·7% (SD 24·3%) for irradiated lesions vs. 1·7% (SD 46·3%) for non-irradiated lesions (p = 0·0008). While abscopal response defined by 30% reduction in any single non-irradiated measurable lesion was present in 26·9% of patients, abscopal response was 13·2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable lesions. Conclusions: iMOSART was well tolerated with acceptable toxicity. Further randomized studies are warranted to investigate the potential clinical benefit of this combination approach. Clinical trial information: NCT02608385