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The rising prevalence of end-stage renal disease and the chronic organ shortage subsequently calls more people upon to consider living kidney donation. The benefits for living donor recipients and the relative low risk of physical complications for donors have been well documented. The risks of impaired quality of life and particularly symptoms of chronic fatigue, however, remain less well understood and dampen the enthusiasm of living kidney donor outcomes.We hypothesized that left-sided donor nephrectomy predisposes donors to symptoms of chronic fatigue due to impairment of blood supply of the left adrenal gland. We retrospectively analyzed 356 living kidney donors undergoing nephrectomy from 1998 to 2013, and aimed to address the impact of donation on physical health and quality of life using the standardized short form-8 questionnaire (SF-8). In addition, we prospectively followed 27 living kidney donors 2014/2015 for symptoms of chronic fatigue. Morning cortisol and ACTH levels were performed at baseline, in the first week, and +6 months post donation. Data were compared between right- and left-sided donation.The response rate amounted to 90.2%. Using a standardized quality of life score, left-sided donors showed a significant worse quality of life compared to right-sided donors (p=0.037). Left-sided donors were more likely to develop symptoms of chronic fatigue and less likely to develop hypertension post donation (p<0.05). Donors with symptoms of fatigue were more likely to be younger and have physically and mentally demanding jobs (p<0.05).Among our prospectively followed donors we identified 4/11 left-sided donors with self-reported fatigue symptoms compared with 1/16 right-sided donors. No differences were observed for morning cortisol and ACTH levels between right-sided and left sided donors at baseline (p>0.05). However, right-sided donors were more likely to show stable morning cortisol levels from pre to +6 months post donation, while left-sided donors showed a decline of morning cortisol levels (p<0.05). While 5/16 right-sided donors developed hypertension in the first-year post donation, no left-sided donor developed hypertension (p=0.059).Our results strongly indicate that the side of donor nephrectomy has major impact on physical and mental quality of life in long-term follow-up. Here, impaired function of the left adrenal gland due to transection of adrenal vessels may result in latent adrenal insufficiency with symptoms of chronic fatigue and less hypertension. The impact of side-selection on long-term outcomes of living donors may greatly influence donor education and the surgical approach to donor nephrectomy.