The purpose of this investigation was to explore the role of uncertainty as a significant variable influencing patients' experiences in illness, treatment, and hospitalization. A theory was proposed on uncertainty in illness. Based upon this conceptualization, a 30-item scale tapping the uncertainty in symptomatology, diagnosis, treatment, relationship with care-givers, and planning for the future was developed. The Mishel Uncertainty in Illness Scale (MUIS) was factor analyzed and two factors were extracted from the data. Replication of the factor analysis provided support for the robustness of each factor. The reliability coefficient for each factor of the MUIS was highly adequate for both the initial and replication analyses. Three validation studies were conducted. Initial support for construct validity of the scale was demonstrated by the finding that the MUIS discriminates between treatment groups according to expected differences. Support for theoretical predictions was evidenced by the significant correlation between the MUIS and stress as measured by the Hospital Stress Events Scale. Convergent validity was supported by the finding that the MUIS correlates significantly with lack of comprehension.