Objectives: This study was conducted to measure the decline in the health-related quality of life (HRQoL) associated with some diseases in South Korean adults. Methods: The EQ-5D health states in the 2005 National Health and Nutrition Examination Survey (NHNES) and the Korean EQ-5D valuation set were used to obtain the EQ-5D indexes of the study subjects. Each disease group was defined when the subjects reported to the NHNES that they were diagnosed with the corresponding disease during the previous 1 year by physicians. Since the distributions of the EQ-5D indexes in each subgroup were negatively skewed, median regression analysis was used to estimate the effects of specific diseases on the HRQoL. Median regression analysis produced estimates that approximated the median of the EQ-5D indexes and there are more robust for analyzing data with many outliers. Results: A total of 16,692 subjects (6,667 patients and 10,025 people without any disease) were included in the analysis. As a result of the median regression analysis, stroke had the strongest impact on the HRQoL for both males and females, followed by osteoporosis, osteoarthritis, rheumatic arthritis, and herniation of an intervertebral disc. While asthma had a significant impact on the HRQoL only in men, cataract, temporo-mandibular dysfunction, and peptic ulcer significantly affected the HRQoL only in women. Conclusions: Stroke and musculoskeletal diseases were associated with the largest losses of the HRQoL in Korean adults.