Purpose: This study compared the quality of life (QOL) of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only. Patients and Methods: Long-term survivors (mean, 10.0 ± 5.3 years after treatment) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast, n = 141, age = 57.0 ± 10.1 years; lymphoma, n = 66, age = 55.8 ± 13.5 years) or local therapy only (breast, n = 294, age = 65.8 ± 9.1 years; lymphoma, n = 37, age = 50.4 ± 12.8 years) were interviewed by phone using the Quality of Life-Cancer Survivors Tool. Results: Multivariate analysis of covariance, controlling for sex, age, education, stage of disease, and time since last treatment, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on overall QOL compared with survivors treated with local therapy only (P = .04). Analysis of covariance on the subscale scores revealed that, compared with survivors who received local therapy, survivors treated with chemotherapy scored significantly lower on the Social subscale (P < .0001), but no differences emerged on the Psychological or Spiritual subscales. There was a statistically significant interaction between treatment and diagnosis (P = .01), as measured by the Physical subscale, indicating that lymphoma survivors treated with chemotherapy scored worse than all other groups. Conclusion: Important QOL differences emerged between the chemotherapy and local therapy groups, suggesting that long-term QOL may vary depending on the type of treatment and diagnosis. © 2005 by American Society of Clinical Oncology.