To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r. Substudy of the prospective, randomized, open-label, multicenter SPIRAL study. Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences. Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median interquartile range (IQR) visceral adipose tissue (VAT) 20.7 (-2.4 to 45.6) cm(2), P = 0.002 and total adipose tissue (TAT) 21.4 (-1.3 to 55.4) cm(2), P = 0.013 were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD 0.01 (0 to 0.02) g/cm(2), P = 0.002, total hip BMD 0.01 (0 to 0.03) g/cm(2), P = 0.015 and total hip T score 0.12 (-0.05 to 0.21) SD, P = 0.004 significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD 0.01 (-0.02 to 0.02) g/cm(2), P = 0.032 and T score 0.01 (-0.18 to 0.18) SD, P = 0.016. Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.