Patients with neuroendocrine neoplasms (NEN) have heterogeneous somatostatin receptor expression with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, e.g. 64Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS), but not overall survival (OS). We hypothesized that the lesion with lowest, rather than highest, 64Cu-DOTATATE uptake would be more prognostic and developed a semi-automatic method for evaluating this. Methods: Patients with NEN underwent 64Cu-DOTATATE PET/CT. A standardized semi-automatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, i.e. lowest of lesion mean standardized uptake values (SUV)mean. Additionally, we assessed total tumor volume derived from the semi-automatic tumor delineation. Kaplan-Meier and Cox regression analyses were used to determine association with OS and PFS. Results: In 116 patients with NEN, median PFS (95% confidence interval) was 23 (20-31) months and median OS was 85 (68-113) months. Minimum SUVmean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, while SUVmax was only significant for PFS. In multivariate Cox analyses, both minimum SUVmean and total tumor volume remained statistically significant. Minimum SUVmean and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: High/low total tumor volume and high/low minimum SUVmean. Patients with low total tumor volume and high minimum SUVmean had a hazard ratio (95% confidence interval) of 0.32 (0.20-0.51) for PFS and 0.24 (0.13-0.43) for OS, both P<0.001 (reference: high total tumor volume and low minimum SUVmean). Conclusion: We propose a standardized semi-automatic tumor delineation method to identify the lesion with lowest 64Cu-DOTATATE uptake and total tumor volume. Assessment of lowest, rather than highest lesion uptake greatly increases prognostication by 64Cu-DOTATATE PET/CT. Combing lesion uptake and total tumor volume, we derived a novel prognostic classification of patients with NEN.