Objectives: This study’s primary aim was to investigate whether meaning-based attitudes to life change during inpatient psychosomatic treatment and the factors influencing the extent of this change. Method: This prospective study ( N = 138) was designed as a naturalistic observation. The effectiveness of treatment was investigated through pre–post comparisons of clinical variables and life attitudes (Life Attitude Profile–Revised) using bivariate tests. Factors influencing the extent of changes in life attitudes were investigated using multivariate regression models. Results: Regarding clinical variables, a small but significant improvement in life attitudes was found, with effect sizes ranging from 0.19 to 0.58. Neuroticism correlated negatively with life attitudes at admission but not significantly with the extent of change in life attitudes. In multivariate models, the extent of the therapeutic relationship and neuroticism correlated positively with the extent of improvement in coherence and self-efficacy. The improvement in self-efficacy was associated with an improvement in life attitudes. Discussion: Although life attitudes are robust characteristics of a person, they change during a hospital psychosomatic treatment, similar to the clinical improvement of symptoms. However, the association between the two is weak. People with stronger neuroticism experience a greater increase in life meaning during hospitalization.