OBJECTIVE The higher incidence of osteoarthritis in females suggests that there may be intrinsic sex-specific differences in human articular chondrocytes. 17beta-Estradiol (E2) regulates rat growth plate chondrocytes through traditional nuclear receptor mechanisms, but only female cells exhibit rapid membrane-associated effects mediated through protein kinase C (PKC) alpha. Here we demonstrate sexual dimorphism in the physiological response of human articular chondrocytes to E2. METHODS Articular chondrocytes were obtained at the time of autopsy from three male and three female donors between 16 and 39 years of age. Second passage cultures were treated with E2 for 24 h to assess the effects of the hormone on [3H]-thymidine incorporation, [35S]-sulfate incorporation, and alkaline phosphatase specific activity. In addition, the chondrocytes were treated for 3, 9, 90 or 270 min and PKC specific activity was determined. RESULTS All chondrocytes were positive for aggrecan and estrogen receptor alpha mRNAs but were negative for type II collagen mRNA. Only cells from female donors responded to E2. DNA synthesis, sulfate incorporation and alkaline phosphatase activity were increased. E2 caused a rapid increase in PKC activity in the female cells within 9 min that was maximal at 90 min. Treatment with the PKC inhibitor chelerythrine blocked these effects. CONCLUSIONS These results provide the first definitive evidence that normal human cells exhibit an intrinsic sex-specific response to E2 and suggest that sexual dimorphism may be an important variable in assessing the pathways that modulate cell behavior.