This study estimated the incidence of malignancy in patients with multiple sclerosis (MS) versus a matched general population cohort in the Netherlands. Adults with a diagnosis of MS between 2006 and 2014 in the General Practitioner (GP) Database of the PHARMO Database Network with ≥ 1 year of patient history were matched to four non-MS individuals based on year of birth, sex, and GP practice. Patients were followed-up until the earliest malignancy diagnosis, death, or end of data collection. Age-adjusted incidence rates (IR) were measured overall and by cancer type. Standardized incidence ratios (SIR) were calculated as the ratio of stratification-specific IRs in the MS and non-MS cohorts. A total of 1,692 MS patients were matched to 6,768 non-MS patients. Age-adjusted IR of any malignancy, excluding non-melanoma skin cancer (n = 27), in the MS cohort was 48.3 (95%CI:30.1–66.5) per 10,000 PY. An increased incidence of any malignancy was observed in the MS cohort versus the non-MS cohort (SIR 1.8 [95%CI:1.1–2.5]). The most commonly observed malignancies in the MS cohort were breast cancer (n = 8; IR 20.4 [95%CI:6.3–34.5] per 10,000 PY) and melanoma (n = 6; IR 14.8 [95%CI:3.0–26.7] per 10,000 PY). The corresponding SIR observed between cohorts was 1.4 (95%CI:0.4–2.4) and 3.4 (95%CI:0.7–6.2), respectively. While the small increased incidence of malignancy in the MS cohort could be an artefact created by a different distribution of risk factors, an increased incidence of malignancy in MS patients in the Netherlands cannot be excluded.