Background: The time course of changes in health-related quality of life (HRQOL) following discharge from the ICU and during a general ward stay has not been studied. We therefore studied the immediate impact of critical illness on HRQOL and its recovery over time. Methods: In a prospective study, all patients admitted to the ICU for > 48 h who ultimately survived to follow-up at 6 months were included. The Medical Outcomes Study 36-item short form was used to measure HRQOL before ICU admission, at discharge from the ICU and hospital, and at 3 and 6 months following discharge from the ICU and hospital. An age-matched healthy Dutch population was used as a reference. Results: Of the 451 included patients, 252 could he evaluated at 6 months (40 were lost to follow-up, and 159 died). Pre-ICU admission HRQOL in survivors was significantly worse compared to the healthy population. Patients who died between ICU admission and long-term follow-up had significantly worse HRQOL in all dimensions already at ICU admission when compared to the long-term survivors. HRQOL decreased in all dimensions (p < 0.001) during ICU stay followed by a rapid improvement during hospital stay, gradually improving to near pre-ICU admission HRQOL at 6 months following ICU discharge. Physical functioning (PF), general health (GH), and social functioning (SF) remained significantly lower than pre-ICU admission values. Compared to the healthy Dutch population, ICU survivors had significantly lower HRQOL 6 months following ICU discharge (except for the bodily pain score). Conclusions: A sharp multidimensional decline in HRQOL occurs during ICU admission where recovery already starts following ICU discharge to the general ward. Recovery is incomplete for PF, GH, and SF when compared to baseline values and the healthy population.