Objective The present study aimed to early identify patients with persistent somatic symptoms (PSS) in primary care by exploring routine care data-based approaches. Design/setting A cohort study based on routine primary care data from 76 general practices in the Netherlands was executed for predictive modelling. Participants Inclusion of 94 440 adult patients was based on: at least 7-year general practice enrolment, having more than one symptom/disease registration and >10 consultations. Methods Cases were selected based on the first PSS registration in 2017-2018. Candidate predictors were selected 2-5 years prior to PSS and categorised into data-driven approaches: symptoms/diseases, medications, referrals, sequential patterns and changing lab results; and theory-driven approaches: constructed factors based on literature and terminology in free text. Of these, 12 candidate predictor categories were formed and used to develop prediction models by cross-validated least absolute shrinkage and selection operator regression on 80% of the dataset. Derived models were internally validated on the remaining 20% of the dataset. Results All models had comparable predictive values (area under the receiver operating characteristic curves=0.70 to 0.72). Predictors are related to genital complaints, specific symptoms (eg, digestive, fatigue and mood), healthcare utilisation, and number of complaints. Most fruitful predictor categories are literature-based and medications. Predictors often had overlapping constructs, such as digestive symptoms (symptom/disease codes) and drugs for anti-constipation (medication codes), indicating that registration is inconsistent between general practitioners (GPs). Conclusions The findings indicate low to moderate diagnostic accuracy for early identification of PSS based on routine primary care data. Nonetheless, simple clinical decision rules based on structured symptom/disease or medication codes could possibly be an efficient way to support GPs in identifying patients at risk of PSS. A ...