A high-pressure P21/c-C2/c phase transition in a synthetic iron-free clinopyroxene of composition Ca0.5Mg1.5Si2O6 was observed at pressure between 3 and 5 GPa from powder diffraction data collected up to P = 14.2 GPa in a diamond anvil cell by means of synchrotron radiation. The transition is marked by a continuous decrease in a, c, and β cell parameters in the transition range and by the disappearance of reflections with h+k odd. No hysteresis could be found. The spontaneous strain due to the transition occurs almost completely on the (010) plane and is described by a strong compression at a direction of 150° from the c axis and a milder expansion at 60° from the c axis. Interaction between the macroscopic cell strain and microscopic strain due to compositional heterogenities may explain the difference from the transition behavior in clinoenstatite. A third-order Birch-Murnaghan equation of state for the C2/c high-pressure phase was refined giving the following parameters: V0 = 429(2) Å3, K = 99(7) GPa, K′ = 6.5 (wχ2 = 1.3). Only minor differences are observed with other iron-free clinopyroxenes. The compressional strain in the C2/c phase in the Ca0.5Mg1.5Si2O6 pyroxene has almost the same orientation as in diopside and in Ca0.8Mg1.2Si2O6 pyroxene, displaying higher compression on (010) at 140° from the c axis and suggesting a similar compressional mechanism for Ca-rich C2/c clinopyroxenes.