AbstractThe important anti‐cancer agent cyclophosphamide and its derivatives have been subjected to 22 crystal structure determinations, 19 of which are unique, revealing 24 independent molecules. These crystal structures show a general preference for chair conformations of the six‐membered ring but unexpected occurrence of boat and half‐chair forms, placement of the exocyclic oxygen atom that is more often axial than equatorial, flattening at the nitrogen atom of the oxazaphosphorinane ring, and a preference for antiperiplanar NCCC1 torsion angles in theN‐chloroethyl groups. Calculations are reported here that demonstrate the suitability of semi‐empirical molecular orbital methods for these systems and evaluate the energy and geometry of the molecules after optimization.Optimization of geometry with the semi‐empirical molecular orbital program, MOPAC, yielded torsion angles and ring puckering generally closer to the crystal structure and the result of ab‐initio optimization when the PM3 Hamiltonian was employed rather than AMI. However, AMI generally predicted an axial disposition of the exocyclic P = O bond, as found in the majority of crystal structures, while PM3 did not. The chair conformation of the ring is preferred, but boat and half‐chair forms are only 1–3 kcal mol−1higher in energy, as are alternative arrangements of the exocyclic P = O bond. Dipole moments usually increase when this bond is made equatorial; thus interaction with a polar solvent could mitigate the energy disadvantage o