Introduction: Elevated serum high sensitivity C-reactive protein (hsCRP) has been reported in established osteoarthritis (OA). The aim of this study was to determine whether serum levels of hsCRP are associated with the variation in tibial and patella cartilage volumes in women without evidence of OA. Methods: Participants were recruited from a database established from the Australian electoral roll, and were aged 40 to 67 years, were not hysterectomized and had no significant knee pain or knee injury in the last 5 years. Tibial and patella cartilage volumes were measured from magnetic resonance imaging (MRI) of each woman's dominant knee and hsCRP measured in serum. Linear regression models were used to explore the major determinants of variation in both tibial and patella cartilage volume and to assess whether serum hsCRP made an independent contribution to variation in the volumes of cartilage in the two knee compartments. Results: The mean age of the 176 participants was 52.3 ± 6.6 years. Compared with a standard model for tibial cartilage volume that included bone area, age, smoking and alcohol status, the addition of an hsCRP term made an independent negative contribution to variation in tibial cartilage volume, irrespective of whether body mass index (BMI) was included in the model or not. By contrast, using a similar approach, hsCRP did not contribute independently to variation in patella cartilage volume. Conclusion: In asymptomatic women aged 40 to 67 years, serum hsCRP is independently negatively associated with the volume of tibial but not patella cartilage suggesting that subclinical inflammation may predispose to knee cartilage loss in the tibial compartment. This should be further assessed by a longitudinal study.