Objective: A woman's health-related quality of life (HRQoL) can be affected by her premenstrual symptoms. The study objective was to assess the association between HRQoL and score differences on the Premenstrual Symptoms Impact Survey (PMSIS), a six-item instrument for measuring impact of premenstrual symptoms on a woman's HRQoL. Methods: Data were collected on the PMSIS and SF-12 Health Survey from a panel of representative U.S. women 18-45 years via Internet (N=971). PMSIS scores were used to identify women “at risk for PMDD.” Items from the SF-12 were dichotomized and regressed onto the standardized PMSIS scores with age as a covariate. Logistic regression was used to derive odds ratios (OR) for experiencing a particular outcome as a function of score differences between “at risk for PMDD” and the population mean of the PMSIS. Results: The overall sample mean PMSIS score was 26.6 (on a standardized scale of 0-100 from no impact to severe impact). Higher PMSIS scores were significantly associated with increased risk of negative HRQL outcomes (p<0.01). Women identified as “at risk for PMDD” (PMSIS score = 64) had 383% increased risk of pain interfering with normal work; 320% increased risk of doing work or activities less carefully than usual due to emotional problems; 253% increased risk of feeling limited in work or activities due to physical health or feeling they accomplished less due to emotional problems; and 196% increased risk of feeling downhearted and depressed, and feeling little or no energy. Conclusion: There is a significant association between higher PMSIS scores (more severe impact due to premenstrual symptoms) and diminished role functioning, physical and mental health well-being. The PMSIS can be a significant predictor of HRQoL in women with PMDD.