Acute hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, (or a combination of these), and sudden death are well-recognized complications of the cemented hip arthroplasty procedure. Collectively, these are known as the bone cement implantation syndrome (BCIS). The endogenous cannabinoids, anandamide (ANA) and 2-arachidonylglycerol (2-AG), are reported to be strong vasodilators and play a role in the hypotension associated with hemorrhagic and septic shock. In the present study, a potential role for the endogenous cannabinoids in influencing hemodynamic variables in BCIS was investigated. Thirty-five patients (35 hips) entered a prospective, randomized clinical trial. The patients were divided into two groups. Group 1 comprised 16 patients who had the component inserted using a conventional cementing technique, whereas group 2 consisted of 19 patients who had the femoral component inserted without cement. Blood samples were taken at six consecutive time points: before anesthesia, after reaming the femur, 2 min after insertion of stems with or without cement into the femur, and 10 min, 20, and 30 min after stem insertion. In group 1 (with cement), the mean levels of ANA and 2-AG significantly increased after stem insertion. In a comparison of each group after stem insertion, mean ANA and 2-AG levels in group 1 also significantly differed from those in group 2. By contrast, in group 2 (without cement) neither ANA nor 2-AG levels exhibited a significant increase or change at any point in time. In conclusion, we have shown for the first time that endogenous cannabinoids are candidates for lipid mediators of BCIS.