Background: Podoconiosis, lymphatic filariasis (LF) and leprosy are neglected tropical diseases (NTDs) that cause lymphoedema. Morbidity management and disability prevention (MMDP) services have been shown to reduce their physical impacts, but little is known both about how to address the psychosocial needs of patients and how to integrate services into the primary care unit and scale up these interventions in the resource-limited countries where they are most needed. Objectives: To evaluate the clinical (physical), mental health and psychosocial outcomes of an integrated holistic care package for lower limb disorders due to podoconiosis, LF and leprosy in north-western Ethiopia, and to determine the fidelity of implementation of the integrated care package. These objectives were set following a systematic review to identify gaps in knowledge surrounding disability, psychosocial and mental health outcomes of people affected by podoconiosis, LF and leprosy. Methods: For the systematic review we searched papers reporting on disability, psychosocial and mental health outcomes of these three NTDs. Peer-reviewed articles were searched and extracted from Medline, PsychInfo, Global Health and Embase. Data were extracted and narratively summarized, as the studies were heterogenous and used different outcome measures. The review has been published. After baseline data collection, a holistic integrated care package was piloted as part of the EnDPoINT (Excellence in Disability Prevention Integrated across Neglected Tropical Diseases) project in Gusha district, Awi zone, Ethiopia. To assess the acceptability, scalability and sustainability of the care package and barriers to its implementation, a qualitative study was conducted. The qualitative data analysis results have been published. We quantitatively assessed the impact of the care package at three months and twelve months post-initiation by using validated measurement tools. For this, mixed effect linear regression and mixed effect logistic regression were conducted; with a fixed effect for time point and a random effect for participant. The cohort study results have been accepted for publication. Results: During the systematic review, fourteen studies provided evidence on the disability associated with leprosy, podoconiosis or LF. Ten studies provided evidence on the association with mental health or psychosocial outcomes. High burden of mental illness was reported, with prevalence varying from 12.6% to 71.7%. During the baseline study, among the 251 patients with lymphoedema who were included, 119 (47.4%) had moderate to severe depression and overall quality of life (QOL) was poor (mean ± SD DLQI score: 11.4 ± 4.2). Disability was significantly associated with depression (β=0.26; 95% CI: 0.19, 0.33) and poor quality of life (β=−0.08; 95%CI: −0.15, −0.01). In the qualitative study, the integrated lymphoedema care package resulted in improved awareness of the causes, treatment and prevention of lymphoedema and in reduced stigma and discrimination. Barriers to integrated care were unrealistic patient expectations, inadequate dissemination across health workers, and poor transportation access In the quantitative follow-up study, we found significant improvements in both physical and psychosocial outcomes. There was reduction in acute adenolymphangioadenitis (ADLA) (adjusted odds ratio [aOR] was -2.1; 95% confidence interval [CI] -2.5, -1.79; p<0.001), and overall level of disability (mean reduction in WHODAS 2.0 score -11.0; 95% CI -12.1, -9.9; p<0.001). Significant improvements were also notified in QOL (mean difference in adjusted DLQI score -7.2; 95% CI -7.9, 6.5; p<0.001), and depression (mean PHQ-9 score -7.2; 95% CI -7.9, -6.5; p<0.001). Conclusion: There is high burden of disability, and poor psychosocial and mental health outcomes associated with podoconiosis, LF and leprosy. Health professionals, decision makers and patients believed the integrated lymphoedema care package to be acceptable, and potentially scalable and sustainable. Following implementation of the integrated holistic care package there was significant improvement in both physical and psychosocial-mental health outcomes. This research provides evidence that the EnDPoINT care package is effective across a range of physical and psychosocial outcomes. Following itsscale-up and cost-effectiveness assessment in three more districts, we recommend it to be scaled up to other endemic districts in Ethiopia and elsewhere.