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Abstract The aim of this study was to evaluate the influence of implant macrodesign and surface hydrophilicity on osteoclast (OC) differentiation, activation, and survival in vitro. Titanium disks were produced with a sandblasted, dual acid-etched surface, with or without additional chemical modification for increasing hydrophilicity (SAE-HD and SAE, respectively) and different macrodesign comprising trapezoidal (HLX) or triangular threads (TMX). This study evaluated 7 groups in total, 4 of which were experimental: HLX/SAE-HD, HLX-SAE, TMX/SAE-HD, and TMX/SAE; and 3 control groups comprising OC differentiated on polystyrene plates (CCPC): a positive CCPC (+), a negative CCPC (–), and a lipopolysaccharide-stimulated assay positive control group, CCPC-LPS. Murine macrophage RAW264.7 cells were seeded on the disks, differentiated to OC (RAW-OC) by receptor activator of nuclear factor-κB ligand (RANKL) treatment and cultured for 5 days. Osteoclast differentiation and cell viability were respectively assessed by specific enzymatic Tartrate-Resistant Acid Phosphatase (TRAP) activity and MTT assays. Expression levels of various OC-related genes were measured at the mRNA level by quantitative polymerase chain reaction (qPCR). HLX/SAE-HD, TMX/SAE-HD, and HLX/SAE significantly suppressed OC differentiation when compared to CCPC (+). Cell viability was significantly increased in TMX/SAE and reduced in HLX/SAE-HD. In addition, the expression of Interleukin (IL)-6 and Tumour Necrosis Factor (TNF)-α was upregulated in TMX/SAE-HD compared to CCPC (+). Hydrophilic surfaces negatively modulate macrophage/osteoclast viability. Specifically, SAE-HD with double triangular threads increases the cellular pro-inflammatory status, while surface hydrophilicity and macrodesign do not seem to have a distinct impact on osteoclast differentiation, activation, or survival. (OC activation vitro sandblasted acidetched acid etched SAEHD SAE HD HLX (HLX TMX. TMX . (TMX) total experimental HLX/SAEHD, HLXSAEHD HD, HLX/SAE-HD HLXSAE, HLXSAE HLX-SAE TMX/SAEHD, TMXSAEHD TMXSAE (CCPC) +, + , (+) –, – (–) lipopolysaccharidestimulated lipopolysaccharide stimulated group CCPCLPS. CCPCLPS LPS. LPS CCPC-LPS RAW2647 RAW RAW264 RAW264. RAWOC (RAW-OC factorκB factor κB RANKL (RANKL days TartrateResistant Tartrate Resistant TRAP (TRAP assays OCrelated related qPCR. qPCR (qPCR) +. HLX/SAEHD. HD. addition IL6 IL 6 (IL)- TNFα TNF α TMX/SAEHD macrophageosteoclast Specifically proinflammatory pro inflammatory status (TMX HLX/SAEHD (CCPC (+ (– RAW26 (qPCR (IL) ( RAW2 (IL