This study investigated factors influencing heifer replacement and cow–calf profitability using 361 cows (born 2011–2018) at the Lacombe Research and Development Centre, Alberta, Canada. Profitability was measured by marginal returns (MR) incorporating feed costs, heifer opportunity cost, calf and cull revenues, and a premium for cows retained in the herd. The study evaluated the linear effects of lifetime productivity, feed efficiency (residual feed intake adjusted for off-test backfat thickness; RFI_fat), and genomic retained heterozygosity, an indicator of heterosis, on MR, feed costs, total costs, and net revenue (NR). Lifetime productivity, defined by the cumulative weight of calves weaned, was positively associated with MR and NR (P < 0.01). RFI_fat influenced total cost, MR, and NR (P < 0.05), with MR improved by $168.50 cow⁻¹ year⁻¹ for each unit decrease in RFI_fat, although regression and group mean comparisons were not fully consistent. Genomic retained heterozygosity positively impacted MR and NR, with a 10% increase enhanced MR and NR by $21.80 and $20.50 cow⁻¹ year⁻¹, respectively. Cow breed type did not affect longevity, MR, or NR. In conclusion, RFI_fat and genomic diversity were important factors to consider in heifer replacement decisions when lifetime DMI was estimated as described in the present study.