Objectives: The aim of the presented study was to compare the health locus of control (HLC) between employed and unemployed patients after kidney transplantation (KT), and to investigate the relationship between HLC and the quality of life (QoL). Material and Methods: The study group consisted of 101 KT patients and the control group of 60 hemodialysis (HD) patients. The applied methods were: the Multidimensional Health Locus of Control Questionnaire (MHLC), the WHO Quality of Life Questionnaire (WHOQoL-BREF), and a survey collecting information on the socio-demographic status and work experience. Results: Overall, 57.5% of KT patients were employed and 42.5% were unemployed. In the HD group, 25% were employed and 71% were unemployed, while 4% did not disclose their employment status. The unemployed KT patients, in comparison with the employed ones, presented a higher feeling of the impact of chance on their health (unemployed M±SD 23.68±6.59; employed M±SD 21.02±4.57) and a lower level of QoL on the Somatic Scale (unemployed Me = 14.00, IQR = 3.00; employed Me = 1450, IQR = 3.00) and the Environmental Scale (unemployed M±SD 15.39±2.83; employed M±SD 16.85±3.24). In the employed KT group, the Internal Control Scale (MHLC) correlated with all QoL scales (the Somatic Scale: r = 0.292, p = 0.036; the Psychological Scale: r = 0.455, p = 0.001; the Social Scale: r = 0.304, p = 0.029; and the Environmental Scale: r = 0.307, p = 0.027). In the unemployed KT group, the Internal Control Scale (MHLC) correlated significantly with the Somatic Scale (r = 0.396, p = 0.013) and the Psychological Scale (r = 0.374, p = 0.019). Conclusions: The employed KT patients have a higher level of independence, with results indicating a strong internal type. Additionally, the working patients assess their QoL better, both in terms of their health condition and the organization of satisfying environment. The obtained knowledge about the psychological characteristics of KT patients may be useful for the occupational activation programs and psycho-education for those with weaker predispositions. Int J Occup Med Environ Health. 2022;35(1):53–62