A comprehensive numerical study on the linear stability of mixed-convection flow in a vertical pipe with constant heat flux is presented with particular emphasis on the instability mechanism and the Prandtl number effect. Three Prandtl numbers representative of different regimes in the Prandtl number spectrum are employed to simulate the stability characteristics of liquid mercury, water and oil. The results suggest that mixed-convection flow in a vertical pipe can become unstable at low Reynolds number and Rayleigh numbers irrespective of the Prandtl number, in contrast to the isothermal case. For water, the calculation predicts critical Rayleigh numbers of 80 and −120 for assisted and opposed flows, which agree very well with experimental values of Rac = 76 and −118 (Scheele & Hanratty 1962). It is found that the first azimuthal mode is always the most unstable, which also agrees with the experimental observation that the unstable pattern is a double spiral flow. Scheele & Hanratty's speculation that the instability in assisted and opposed flows can be attributed to the appearance of inflection points and separation is true only for fluids with O(1) Prandtl number. Our study on the effect of the Prandtl number discloses that it plays an active role in buoyancy-assisted flow and is an indication of the viability of kinematic or thermal disturbances. It profoundly affects the stability of assisted flow and changes the instability mechanism as well. For assisted flow with Prandtl numbers less than 0.3, the thermal–shear instability is dominant. With Prandtl numbers higher than 0.3, the assisted-thermal–buoyant instability becomes responsible. In buoyancy-opposed flow, the effect of the Prandtl number is less significant since the flow is unstably stratified. There are three distinct instability mechanisms at work independent of the Prandtl number. The Rayleigh–Taylor instability is operative when the Reynolds number is extremely low. The opposed-thermal–buoyant instability takes over when the Reynolds number becomes higher. A still higher Reynolds number eventually leads the thermal–shear instability to dominate. While the thermal–buoyant instability is present in both assisted and opposed flows, the mechanism by which it destabilizes the flow is completely different.