Background Major lower limb amputation results in a profound change in a patient`s way of life. Patients adapt to this change differently. Amputation leaves a significant burden on both the individual and society. Knowing factors contributing to adaptation can be one of strategies in ensuring good mobility and quality of life. The focus of this study was how patients adapt to this change. There are anecdotal reports on how major lower limb amputees adapt to new life after amputation in Sub Sahara Africa and Tanzania in general. Objectives This study aimed to determine the factors contributing to adaptation to major lower limb amputations in KCMC, Moshi, Northern Tanzania. Methods This was a cross sectional hospital-based study conducted in Sept 2013-May 2014. Questionnaires were used during face to face interview and observation during 6MWT, EQ5-D, EQ-VAS to collect necessary information among amputees attending Orthopaedic and general surgery OPD in KCMC during the study period. Data were entered, cleaned and analysed using SPSS version 20. Frequency, proportion and percentage to describe categorical variables, central tendency and respect measure of dispersion used to summarize continuous variables. Chi-square test was used to assess significance of predictive variables for functional and quality of life. Results Of 53 major lower limb amputees recruited for this study median age was 42 years ranging between 19 and 82 years. Male gender constituted high percentage (58.5% n=31), more than half of the clients enrolled in this study (55.6% n=30) had major lower limb amputation due to accident/trauma and (18.5% n=9) had amputation due to diabetes. More than half of study participants (60.4% n=32) had transtibia followed by transfemoral which was presented by slightly more than one third of all participants (37.7% n=20). Almost half of study participants reported stump pain after amputation (48% n=26) and slightly less than half of participants (47% n=25) reported to have phantom pain, only 5% had stump ulcers. Traumatic and transfemoral amputees and being female were associated with higher level of anxiety/depression. Having diabetes mellitus was significantly associated with reporting problems with self-care and performing usual activities (P<0.05). Having transtibia amputation was significantly associated with reporting any problem with mobility, usual care, pain/discomfort and anxiety/depression (P<0.001). Female suffered from more reactive depression and anxiety symptoms than males. Overall, more than half of study participants (60.4%) had no problem in walking. The number of major lower limb amputees who had prosthesis were 83%, and those who use prosthesis were 93.2%. Those who wore prosthesis more than 8 hours per day were 62.8%. Low levels of anxiety/depression and pain/discomfort, living at home were 94.3%, good social support, having normal body mass index by 55%. About 70.2% of amputees were able to walk 200-600meters in six minute walk test. Conclusion Generally, this study has shown that three quarters of amputees who received care at KCMC had good adaptation. The factors contributed to good adaptation in this study were male gender, good social support, low levels of anxiety/depression, good mobility scores, having prosthesis and able to walk with prosthesis for >8hours and having normal body mass index. However factors associated with poor adaptation among amputees who undergone major lower limb amputations in this study were female gender, being trans femoral amputees following trauma/accident, stump pain, phantom pain and diabetes mellitus. The most affected age group was younger adults. Transtibia was the leading level of amputation by more than half of study participants. These factors can then be an area of focus in the peri-operative and rehabilitation period.