Context: Clinicians are urged to document patient-based outcomes during rehabilitation to measure health-related quality of life (HRQOL) from the patient's perspective. It is unclear how scores on patient-reported outcome instruments (PROs) vary over the course of an athletic season because of normal athletic participation.Objective: Our primary purpose was to evaluate the effect of administration time point on HRQOL during an athletic season. Secondary purposes were to determine test-retest reliability and minimal detectable change scores of 3 PROs commonly used in clinical practice and if a relationship exists between generic and region-specific outcome instruments.Design: Cross-sectional study. Setting: Athletic facility.Patients or Other Participants: Twenty-three collegiate soccer athletes (11 men, 12 women).Main Outcome Measure(s): At 5 time points over a spring season, we administered the Disablement in the Physically Active Scale (DPA), Foot and Ankle Ability Measure-Sport, and Knee Injury and Osteoarthritis Outcome Score (KOOS).Results: Time effects were observed for the DPA (P ¼ .011) and KOOS Quality of Life subscale (P ¼ .027). However, the differences between individual time points did not surpass the minimal detectable change for the DPA, and no post hoc analyses were significant for the KOOS-Quality of Life subscale. Test-retest reliability was moderate for the KOOS-Pain subscale (intraclass correlation coefficient ¼ 0.71) and good for the remaining KOOS subscales, DPA, and Foot and Ankle Ability Measure-Sport (intraclass correlation coefficients . 0.79). The DPA and KOOS-Sport subscale demonstrated a significant moderate relationship (P ¼ .018).Conclusions: Athletic participation during a nontraditional, spring soccer season did not affect HRQOL. All 3 PROs were reliable and could be used clinically to monitor changes in health status throughout an athletic season. Our results demonstrate that significant deviations in scores were related to factors other than participation, such as injury. Finally, both generic and region-specific instruments should be used in clinical practice.Key Words: health-related quality of life, patient-centered outcomes, injury history, evidence-based practice Key PointsThe Disablement in the Physically Active Scale, Foot and Ankle Ability Measure-Sport, and Knee Injury and Osteoarthritis Outcome Score scales are reliable instruments that have been used clinically to assess activity limitations and participation restrictions in collegiate athletes. Significant changes in health-related quality of life are likely to be associated with an injury that restricts athletic participation or another factor rather than participation itself. To capture all dimensions of health-related quality of life, clinicians should use both a generic and a region-specific instrument.