Prostaglandins are known to be involved in the metabolism of bone, having a significant influence on bone resorption in cases of bone pathology. We therefore investigated the short-term effects of two commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and acetaminophen (paracetamol), on bone resorption in healthy men. In a randomized, double-blind pilot study, 28 healthy, age- and weight-matched male volunteers were treated with ibuprofen (n = 10), acetaminophen (n = 9), or a placebo (n = 9) for 3 days. As an indication of bone resorption rate, levels of the biochemical bone markers N-telopeptide (NTx) and free deoxypyridinoline (D-Pyr) were measured in urine. Differences in resorption marker levels pre- and post-NSAID use were then compared between groups. We found that NTx concentrations in the acetaminophen group were lower than placebo (p = 0.048), whereas NTx levels in the ibuprofen group were higher than in the acetaminophen group (p = 0.016). By contrast, D-Pyr concentrations in the ibuprofen group were significantly lower than in the placebo group (p = 0.009). A comparison of the percentage changes of D-Pyr:NTx ratios found that the ratio in the ibuprofen group was significantly lower than that of both the control (p = 0.0065) and acetaminophen (p = 0.01) groups. These results show the differential effects of ibuprofen and acetaminophen on urinary excretion of peptide-bound and free deoxypyridinoline cross-links of type I collagen. Short-term ibuprofen use may alter the renal handling of collagen cross-links and increase bone resorption to a greater extent than acetaminophen in normal men.