The effect of pressure on the helix-coil transition temperature (Tm) is reported for the double-stranded polymers poly(dA)poly(dT), poly[d(A-T)], poly[d(l-C], and poly[d(G-C] and triple-stranded poly(dA)2poly(dT). The Tm increases as a function of pressure, implying a positive volume change for the transition and leading to the conclusion that the molar volume of the coil form is larger than the molar volume of the helix. From the change in Tm as a function of pressure, molar volume changes of the transition (ΔVt) are calculated using the Clapeyron equation and calorimetrically determined enthalpies. For the doublestranded polymers, ΔVt, increases in the order poly[d(l-C] < polyt[d(A-T)] < poly(dA)-poly(dT) < polylcl(G-C)]. The value of ΔVt, for the triple-stranded to single-stranded transition of poly(dA) 2poly(dT) is larger than that of poly[d(G-C)I. The magnitude of ΔVt increases with salt concentration in all cases studied; however, the change of ΔVt with salt concentration depends on the sequence of the DNA and the number of strands involved in the transition. In the model proposed to explain the results, the overall molar volume change of the transition is a function of a negative volume change arising from changes in the electrostatic interactions of the DNA strands, and a positive volume change due to unstacking the bases. The model predicted the direction of the change in the ΔVt for several experiments. The magnitude of AVJ increases with counter ion radius, thus for polyld(A-T)], ΔVt, increases in the series Na+ , K+, Cs+, The ΔVt also increases if the charge on the phosphodiester groups is removed. The kinetics of the formation of double-stranded (dA)19(dT)19 in 50 mM NaCI are slowed approximately 14-fold at 200 MPa relative to atmospheric pressure. The implied volume of activation of +37 ml mol−l in the direction of this change is also in agreement with the proposed model. The stability of double- and triple-stranded DNA helices in water around neutral pH depends on the base composition and sequence, as well as on the ionic strength of the solution. Each of these dependencies also defines how DNA interacts with water.