Abstract Purpose This study investigated the effect of the “Screening for Distress and Referral Need” (SDRN) process (completing a screening instrument; patient-caregiver discussion about the patient’s responses, regardless of distress level, and possible referral to specialized care), implemented in Dutch oncology practice on patient-reported outcomes (PROs). Methods A non-randomized time-sequential study was conducted to compare two cohorts. Cohort 1 respondents (C1) were recruited before and cohort 2 respondents (C2) after SDRN implementation in nine Dutch hospitals. Participants completed the EORTC-QLQ-C30, HADS, Patient Satisfaction Questionnaire-III, and the Distress Thermometer and Problem List (DT&PL). Descriptive analyses and univariate tests were conducted. Results C2 respondents ( N = 422, response = 54%) had significantly lower mean scores on the practical ( t = 2.3; p = 0.02), social ( t = 2.3; p = 0.03), and emotional PL domains ( t = 2.9; p = 0.004) compared with C1 ( N = 518, response = 53%). No significant differences were found on quality of life, anxiety, depression, satisfaction with care, distress level, the spiritual and physical PL domains, or on referral wish. Conclusions After implementation of SDRN, patients report significantly fewer psychosocial (practical, social, and emotional) problems on the DT/PL but responses on the other patient-reported outcomes were comparable. These results add to the mixed evidence on the beneficial effect of distress screening. More and better focused research is needed.