The development and maintenance of healthy joints is a complex process involving many physical and biological stimuli. This study investigates the interaction between insulin-like growth factor-I (IGF-I) and static mechanical compression in the regulation of articular cartilage metabolism. Bovine cartilage explants were treated with concentrations of IGF-I from 0 to 300 ng/ml in the presence or absence of 0–50% static compression, and the transient and steady-state incorporation of [³H]proline and [³⁵S]sulfate into matrix components were measured. In parallel studies, cartilage explants were treated with 0–300 ng/ml IGF-I at media pH ranging from 6.4 to 7.2 and the steady-state incorporation of [³H]proline and [³⁵S]sulfate was measured. The effect of 50% static compression on IGF-I transport was determined by measuring the uptake of ¹²⁵I-labeled IGF-I into cartilage explants. Static compression decreased both [³H]proline and [³⁵S]sulfate incorporation in a dose-dependent manner in the presence or absence of IGF-I. IGF-I increased [³H]proline and [³⁵S]sulfate incorporation in a dose-dependent manner in the presence or absence of compression, but the anabolic effect of the growth factor was lessened when the tissue was compressed by 50%. The response of cartilage explants to IGF-I was similarly lessened in unstrained tissue cultured in media at pH 6.4, a condition which results in a similar intratissue pH to that when cartilage is compressed by 50%. The characteristic time constant (τ) for IGF-I stimulation of cartilage explants was approximately 24 h, while τ for inhibition of biosynthesis by static compression was approximately 2 h. Samples which were both compressed and treated with IGF-I demonstrated an initial decrease in biosynthetic activity at 2 h, followed by an increase at 24 h. Static compression did not alter τ for ¹²⁵I-labeled IGF-I transport into cartilage but decreased the concentration of ¹²⁵I-labeled IGF-I in the tissue at equilibrium.