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On the medical images, many of the tissues/lesions may be ambiguous. That is why the medical segmentation is typically annotated by a group of clinical experts to mitigate the personal bias. However, this clinical routine also brings new challenges to the application of machine learning algorithms. Without a definite ground-truth, it will be difficult to train and evaluate the deep learning models. When the annotations are collected from different graders, a common choice is majority vote. However such a strategy ignores the difference between the grader expertness. In this paper, we consider the task of predicting the segmentation with the calibrated inter-observer uncertainty. We note that in clinical practice, the medical image segmentation is usually used to assist the disease diagnosis. Inspired by this observation, we propose diagnosis-first principle, which is to take disease diagnosis as the criterion to calibrate the inter-observer segmentation uncertainty. Following this idea, a framework named Diagnosis First segmentation Framework (DiFF) is proposed to estimate diagnosis-first segmentation from the raw images.Specifically, DiFF will first learn to fuse the multi-rater segmentation labels to a single ground-truth which could maximize the disease diagnosis performance. We dubbed the fused ground-truth as Diagnosis First Ground-truth (DF-GT).Then, we further propose Take and Give Modelto segment DF-GT from the raw image. We verify the effectiveness of DiFF on three different medical segmentation tasks: OD/OC segmentation on fundus images, thyroid nodule segmentation on ultrasound images, and skin lesion segmentation on dermoscopic images. Experimental results show that the proposed DiFF is able to significantly facilitate the corresponding disease diagnosis, which outperforms previous state-of-the-art multi-rater learning methods.