Key PointsQuestionDoes a stepped collaborative care intervention including psychotherapy or pharmacotherapy delivered via telehealth improve symptoms of fatigue, pain, or depression among patients with end-stage kidney disease (ESKD) who are undergoing long-term hemodialysis?FindingsThis randomized clinical trial of 160 patients with ESKD undergoing hemodialysis with at least moderate levels of fatigue, pain, or depression found that treatment with a stepped collaborative care intervention delivered during hemodialysis or at home vs health education control resulted in clinically significant improvements in fatigue and pain.MeaningThese findings show that this stepped collaborative care intervention is a significantly effective treatment for fatigue and pain in patients undergoing long-term hemodialysis for ESKD.