Some classes of drugs have lower than optimal uptake of generic products. We aimed to understand the determinants of generic drug substitution across classes.We conducted a cross-sectional analysis of data from the 2013 MarketScan Commercial Claims and Encounters Database from Truven Health Analytics. We quantified generic substitution rates (GSR) for 26 drug classes, choosing one representative week in November 2013. We used mixed-effects logistic regression to estimate the independent relationship between the determinants of interest and generic substitution for 8 classes with low generic utilization.The GSRs for most classes exceeded 90%, although some were much lower including thyroid hormones (64%), androgens (74%), estrogens (71%), and hydantoin-type anticonvulsants (72%). The determinants of generic substitution varied across classes, albeit with important patterns. Patients using a mail order pharmacy had significantly less generic substitution than patients filling at retail pharmacies for 5 of the 8 studied classes; two additional classes showed no relationship between pharmacy type and generic use. Men relative to women and patients taking more medications were more likely to use generics for most classes. State substitution laws and patient consent laws were largely inconsequential regarding generic substitution.Policies are needed to support the use of safe, effective and often lower cost generic drugs, when available. Mail order pharmacies, as often required by pharmacy benefits managers, lessen generic use for many classes. These pharmacies may require additional regulatory oversight if this adversely impacts patients.