Background: Oncologists accurately identify only 35% of patients with cancer who will die in six months. There is an urgent need for automated, accurate prognostic systems to inform treatment and advance care planning in oncology. We assessed the prospective performance of a previously described ML algorithm (Parikh et al, JAMA Netw Open, 2019) to predict short-term mortality in a cohort of general oncology outpatients. Methods: Our prospective cohort consisted of patients aged ≥18 years who had a medical or gynecologic oncology encounter between March 1 and April 30, 2019 in either a tertiary academic practice or one of twelve community practices within a large academic cancer system. We used a retrospectively validated gradient-boosting ML algorithm, based on 559 structured electronic health record (EHR) variables, to predict 180-day mortality prior to each oncology encounter. For patients with multiple encounters, we selected the last encounter to assess performance. We assessed several performance metrics, including area under the receiver operating curve (AUC), area under the precision-recall curve (AUPRC), scaled Brier score (sBrier; a measure of calibration ranging from 0 [random] to 1 [perfect]), and positive predictive value (PPV). Results: Of 25,537 unique patients, median age was 64.4 (interquartile range 53.3 – 73.0), 76.8% were White, 56.5% were treated at a community center, and 4.1% died within 180 days. The ML algorithm had an AUC of 0.89 (95% confidence interval [CI] 0.88-0.90), AUPRC 0.34, and sBrier 0.29. At a prespecified threshold of 40%, observed 180-day mortality was 44.5% (95% CI 40.7 – 48.4%) in the high-risk group vs. 3.0% (95% CI 2.8% – 3.3%) in the low-risk group. There was an 85-fold difference in mortality (13.6% vs. 0.16%) in the top vs. bottom risk quartiles. The model was well-calibrated for mortality risks ≤40% and slightly under-calibrated for mortality risks > 40%. Performance varied across cancer types in the tertiary hospital but did not vary by race or practice type (Table). Conclusions: In this prospective cohort study among outpatients with cancer, a ML prognostic algorithm based on EHR data had better discrimination and calibration that published cancer-specific models. This is one of the first ML prognostic models to be prospectively validated in oncology.