OBJECTIVE: To evaluate chosen serum cytokines and their association with osteoarthritis (OA) in the guinea pig. METHODS: The levels of 18 cytokines were measured in Hartley guinea pig serum at time points ranging from 3 weeks to 18 months of age. These levels were then tested for any correlation with total histology, and a comprehensive evaluation of these statistics was conducted using data previously collected from OA-resistant Strain 13 guinea pigs. RESULTS: After all cytokines demonstrating a significant association with weight or age were excluded, IL-6 (p=0.016) and G-CSF (p=0.024) were found to correlate positively with total histological score. Models involving each of these cytokines paired independently with weight explained 43-44% of the variance in total histology. CONCLUSIONS: Only the age and weight-independent associations of IL-6 and G-CSF with histological OA were significant under the conditions imposed by the Holm step-down adjustment for multiple comparisons. Though the observed changes of these cytokine levels may be due to a correlation with age, it is highly unlikely given the significant difference between Hartley and Strain 13 age-matched cohorts.