Background: Guidelines recommend to prescribe a laxative with an opioid to prevent constipation. We aimed to determine the adherence by general practitioners (GPs) to this recommendation and to explore which GP- and patient related factors were associated with it from the perspective of the GP. Methods: We conducted an observational study using GPs’ prescription data from the Nivel Primary Care Database combined with a questionnaire asking for reasons of non-adherence. The proportion of first opioid prescriptions prescribed together with a laxative was determined as primary outcome. Possible explanatory factors such as the quality of registration, the level of collaboration with the pharmacy, familiarity with the recommendation and use of a clinical decision support system were explored, as were the self-reported reasons for non-adherence (classified as either GP-related or patient-related). We assessed the association of factors with the primary outcome using univariable multilevel logistic regression analysis. Results: The recommendation was measured in 195 general practices. The median proportion of first opioid prescriptions prescribed together with a laxative in these practices was 54% (practice range 18–88%). None of the determinants was consistently associated with the primary outcome. GPs from 211 practices filled out the questionnaire and the most frequently mentioned reason not to prescribe a laxative was that the patient has laxatives in stock, followed by that the patient doesn’t want a laxative; both were patient-related factors. Conclusion: There was room for improvement in following the guideline on laxative prescribing in opioid use. A main reason seemed to be that the patient refuses a laxative. Improvement measures should therefore focus on communication between GPs and patients on the relevance of co-using a laxative with opioids. Future studies need to establish the effect of such improvement measures, and determine whether reasons for non-adherence to the guideline changed over time.