DESIGN, SETTING, AND PARTICIPANTSWe performed univariate and multivariable analyses of 338 lumbar punctures in the Dominantly Inherited Alzheimer Network observational study using linear mixed models, adjusting for participant-level and family-level random effects. MAIN OUTCOMES AND MEASURESWe directly evaluated associations of 3 post-lumbar puncture outcomes (immediate postprocedural headache, PDPH at 24-hour follow-up, and PDPH receiving a therapeutic blood patch) with participant age and sex, positioning, collection method, needle size, needle insertion site, and cerebrospinal fluid (CSF) volume collected. RESULTSThe incidence of adverse events included 73 immediate postprocedural headaches (21.6%), 59 PDPHs at 24-hour follow-up (17.5%), and 15 PDPHs receiving a therapeutic blood patch (4.4%). Greater volume of CSF collected was associated with increased risk of immediate postprocedural headache, largely owing to a nonlinear increase in risk on collection of volumes above 30 mL (odds ratio, 3.73 for >30 mL and 0.98 for <17 mL). In contrast, collection of higher volumes showed a protective effect in decreasing rates of PDPH at 24-hour follow-up and rates of PDPH receiving a therapeutic blood patch (odds ratio, 0.35 per 10 mL). Although differences in needle size did not reach statistical significance, no participant in the 24G needle group received a therapeutic blood patch compared to 8 of 253 for the larger 22G needles. CONCLUSIONS AND RELEVANCEFactors that acutely lower CSF pressure (eg, seated positioning or extracting very high volumes of CSF) may be associated with transient post−lumbar puncture headache, without increasing rates of persistent PDPH or therapeutic blood patch. Collection of up to 30 mL of CSF appears to be well tolerated and safe.