BackgroundComorbidities are common in patients with osteoarthritis (OA). This study aimed to determine the association of a wide range of previously diagnosed comorbidities in adults with newly diagnosed OA compared with matched controls without OA.MethodsA case–control study was conducted. The data were derived from an electronic health record database that contains the medical records of patients from general practices throughout the Netherlands. Incident OA cases were defined as patients with one or more diagnostic codes recorded in their medical records that correspond to knee, hip, or other/peripheral OA. Additionally, the first OA code had to be recorded between January 1, 2006, and December 31, 2019. The date of cases’ first OA diagnosis was defined as the index date. Cases were matched (by age, sex, and general practice) to up to 4 controls without a recorded OA diagnosis. Odds ratios were derived for each 58 comorbidities separately by dividing the comorbidity prevalence of cases by that of their matched controls at the index date.Results80,099 incident OA patients were identified of whom 79,937 (99.8%) were successfully matched with 318,206 controls. OA cases had higher odds for 42 of the 58 studied comorbidities compared with matched controls. Musculoskeletal diseases and obesity showed large associations with incident OA.ConclusionsMost of the comorbidities under study had higher odds in patients with incident OA at the index date. While previously known associations were confirmed in this study, some associations were not described earlier.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13075-023-03086-8.