There are almost no studies about rare diseases in general practice. This study examined care characteristics of active rare disease patients in the Belgian Network of Sentinel General Practices (SGP) and the importance of rare diseases in general practice by its caseload, general practitioner (GP)–patient encounter frequency and nationwide prevalence. The SGP reported data about: (i) the number of active rare disease patients in 2015; and (ii) characteristics of one to three most recently seen patients. Rare diseases were matched against Orphanet (www.orpha.net). GP encounter frequency and patients’ age were compared to the total general practice population. Details from 121 active patients (median age: 44, interquartile range (IQR) 24–60) showed that for 36.9% the GP had been the first caregiver for the rare disease and for 35.8% the GP established a diagnostic referral. GPs rated their knowledge about their patients’ disease as moderate and used Orphanet for 14.9% of patients. Any active rare disease patients (median: 1, IQR 0–2) were reported by 66 of 111 SGP. Compared to the total general practice population, the mean GP encounter frequency was higher (7.3; 95% confidence intervals (CI) 6.1–8.5 versus 5.4; 95% CI 5.4–5.4). The prevalence of rare diseases in the Belgian general practice population was estimated at 12.0 (95% CI 10.3–13.9) per 10,000. This study acknowledges the important role of GPs in rare disease care. Knowledge and use of Orphanet by GPs could be improved.