Surface roughness on implant materials has been shown to be highly influential on the behavior of osteogenic cells. Four surface topographies were engineered on cobalt chromium molybdenum (CoCrMo) in order to examine this influence on human mesenchymal stem cells (MSC). These treatments were smooth polished (SMO), acid etched (AE) using HCl 7.4% and H2SO4 76% followed by HNO3 30%, sand blasted, and acid etched using either 50 μm Al2O3 (SLA50) or 250 μm Al2O3 grit (SLA250). Characterization of the surfaces included energy dispersive X‐ray analysis (EDX), contact angle, and surface roughness analysis. Human MSCs were cultured onto the four CoCrMo substrates and markers of cell attachment, retention, proliferation, cytotoxicity, and osteogenic differentiation were studied. Residual aluminum was observed on both SLA surfaces although this appeared to be more widely spread on SLA50, whilst SLA250 was shown to have the roughest topography with an R a value greater than 1 μm. All substrates were shown to be largely non‐cytotoxic although both SLA surfaces were shown to reduce cell attachment, whilst SLA50 also delayed cell proliferation. In contrast, SLA250 stimulated a good rate of proliferation resulting in the largest cell population by day 21. In addition, SLA250 stimulated enhanced cell retention, calcium deposition, and hydroxyapatite formation compared to SMO (p < 0.05). The enhanced response stimulated by SLA250 surface modification may prove advantageous for increasing the bioactivity of implants formed of CoCrMo. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 3747–3756, 2015.