The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast‐twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1^G93A and SOD1^WT mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1^G93A compared to SOD1^WT mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1^G93A mice (38 ± 7) compared with SOD1^WT controls (95 ± 12); this was attributed to a lower proportion of the most forceful fast‐fatigable (FF) MU in SOD1^G93A mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross‐sectional area (CSA) of serial sections of TA muscles stained with anti‐neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1^G93A, which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity‐dependent fast‐to‐slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast‐twitch muscles of SOD1^G93A mice involves parallel processes: (1) gradual selective motor axon die‐back of the FF motor units that contain large type IIB muscle fibres, and of fatigue‐intermediate motor units that innervate type IID/X muscle fibres, and (2) activity‐dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue‐resistant muscle fibres.