Background: Stereotactic body radiotherapy (SBRT) is a recognized treatment for colorectal cancer (CRC) metastases. We postulated that local responses could be improved by SBRT with a concomitant radiosensitizing agent (irinotecan). Methods: RADIOSTEREO-CAMPTO was a prospective multi-center phase 2 trial investigating SBRT (40–48 Gy in 4 fractions) for liver and/or lung inoperable CRC oligometastases (3), combined with two weekly intravenous infusions of 40 mg/m2 Irinotecan. Primary outcome was the objective local response rate as per RECIST. Secondary outcomes were early and late toxicities, EORTC QLQ-C30 quality of life, local control and overall survival. Results: Forty-four patients with 51 lesions (liver = 39, lungs = 12) were included. Median age was 69 years (46–84); 37 patients (84%) had received at least two prior chemotherapy treatments. Median follow-up was 48.9 months. One patient with two lung lesions was lost during follow-up. Assuming maximum bias hypothesis, the objective local response rate in ITT was 86.3% (44/51—95% CI: [76.8–95.7]) or 82.4% (42/51—95% CI: [71.9–92.8]). The observed local response rate was 85.7% (42/49—95% CI: [75.9–95.5]). The 1 and 2-year local (distant) progression-free survivals were 84.2% (38.4%) and 67.4% (21.3%), respectively. The 1 and 2-year overall survivals were 97.5% and 75.5%. There were no severe acute or late reactions. The EORTC questionnaire scores did not significantly worsen during or after treatment. Conclusions: SBRT with irinotecan was well tolerated with promising results despite heavily pretreated patients.