This study evaluates the influence of different factors in the adaptation process activated by uncertainty in illness on health-related quality of life. The sample included 100 women (mean age = 52.1 years) receiving treatment for newly diagnosed (M = 5.1 months) gynaecological cancer (38 cervical, 26 ovarian, 24 endometrial, 7 uterine, 4 vulvar, and 1 vaginal). Stepwise regression analyses identified mood states, ambiguity about illness-wellness state, danger-focused appraisal and mastery as key predictors of four health-related quality of life scores. The variance accounted for by those variables is reflected in cumulative multiple R2 of 0.56 for total quality of life score, 0.57 for psychosocial well-being, 0.235 for physical well-being and 0.25 for disease/symptom distress. These variances do not reflect the contribution of age, time since diagnosis, metastasis and stage of cancer which were forced to enter the regression equation first. The latter set of variables accounted for a smaller portion of the variance in health-related quality of life (R2 = 0.03-0.195). Coping strategy did not predict health-related quality of life. These findings provide beginning support for conceptualizing health-related quality of life as the outcome of an adaptation process explained by the uncertainty in illness theory. However, uncertainty in illness theory may not be sufficient to predict quality of life outcomes. Future research should consider the addition of discrepancy theory to guide the selection or development of a health-related quality of life measure, to account for the perceived discrepancy between actual experience and expected well-being.